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Malignant Transformation of Giant Cell Tumor of Bone and the Association with Denosumab Treatment: A Radiology and Pathology Perspective

Malignant Transformation of Giant Cell Tumor of Bone and the Association with Denosumab... Hindawi Sarcoma Volume 2022, Article ID 3425221, 11 pages https://doi.org/10.1155/2022/3425221 Research Article Malignant Transformation of Giant Cell Tumor of Bone and the Association with Denosumab Treatment: A Radiology and Pathology Perspective 1 2,3 1 4 K. van Langevelde , A. H. G. Cleven , A. Navas Cañete , L. van der Heijden , 4 5 2 M. A. J. van de Sande , H. Gelderblom , and J. V. M. G. Bovee ´ Department of Radiology, Leiden University Medical Center, Leiden, Netherlands Department of Pathology, Leiden University Medical Center, Leiden, Netherlands Department of Pathology, University Medical Center Groningen, Groningen, Netherlands Department of Orthopedics, Leiden University Medical Center, Leiden, Netherlands Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands Correspondence should be addressed to K. van Langevelde; k.van_langevelde@lumc.nl Received 18 March 2022; Accepted 25 May 2022; Published 17 June 2022 Academic Editor: Kanya Honoki Copyright © 2022 K. van Langevelde et al. �is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Malignancy in giant cell tumor of bone (mGCTB) is categorized as primary (concomitantly with conventional GCTB) or secondary (after radiotherapy or other treatment). Denosumab therapy has been suggested to play a role in the etiology of secondary mGCTB. In this case series from a tertiary referral sarcoma center, we aimed to ‰nd distinctive features for malignant transformation in GCTB on diŠerent imaging modalities. Furthermore, we assessed the duration of denosumab treatment and lag time to the development of malignancy. Methods. From a histopathology database search, 6 patients were pathologically con‰rmed as having initial conventional GCTB and subsequently with secondary mGCTB. Results. At the time of mGCTB diagnosis, 2 cases were treated with denosumab only, 2 with denosumab and surgery, 1 with multiple curettages and radiotherapy, and 1 with surgery only. In the 4 denosumab treated patients, the mean lag time to malignant transformation was 7 months (range 2–11 months). Imaging ‰ndings suspicious of malignant transformation related to denosumab therapy are the absence of ‰bro- osseous matrix formation and absent neocortex formation on CT, and stable or even increased size of the soft tissue component. Conclusion. In 4 patients treated with denosumab, secondary mGCTB occurred within the ‰rst year after initiation of treatment. Radiotherapy-associated mGCTB has a longer lag time than denosumab-associated mGCTB. Close clinical and imaging follow-up during the ‰rst months of denosumab therapy is key, as mGCTB tends to have rapid aggressive behavior, similar to other high- grade sarcomas. Nonresponders should be (re) evaluated for their primary diagnosis of conventional GCTB. types: neoplastic mononuclear stromal cells, macrophages, 1. Introduction and osteoclast-like giant cells. �e neoplastic mononuclear Giant cell tumor of bone (GCTB) typically occurs in young stromal cells express a receptor activator of nuclear factor adults between 20 and 40 years of age after closure of the kappa-B ligand (RANKL) which binds with the RANK re- physis. GCTB arises from the epi-metaphysis and extends up ceptor on osteoclast precursors. Via the RANK-RANKL to the subchondral bone plate [1]. �e 2020 WHO classi- signaling pathway these cells induce osteoclast formation ‰cation of soft tissue and bone tumors [2] de‰nes GCTB as a which gives the typical osteolytic appearance to the tumor locally aggressive tumor that rarely metastasizes. A further [3]. �e incidence of GCTB is 1.66 per million inhabitants division is made into two subtypes: conventional and ma- per year, based on a nationwide pathology database study in lignant GCTB. Conventional GCTB contains three cell the Netherlands. During the 5-year study period, from 2 Sarcoma 13 months on denosumab treatment [21], and in the ischium January 2009 to December 2013, a total of 138 new cases of GCTB were found, with only 1 case of malignant GCTB [1]. with transformation into a high-grade osteosarcoma after 6 months on treatment [18]. However, whether sarcomatous H3F3A gene mutations are detected in at least 95% of giant cell tumors, and 90% of these mutations are repre- transformation in (recurrent) GCTB is a causal or coinci- sented by the H3.3 pGly34Trp mutation [2]. H3.3 pGly34Trp dental phenomenon with regards to the use of denosumab is (H3G34W) immunohistochemistry is a reliable surrogate unclear for these cases, and as yet no biological hypothesis marker for molecular analysis [4]. Within the context of exists that explains the association between denosumab bone tumors, this marker is highly specific for GCTB. treatment and malignant transformation. (e primary treatment for GCTB is surgical excision. In this case series, we aim to give an overview of mGCTB patients from our tertiary referral center (Leiden University (e rate of local recurrence depends on the type of surgery performed and ranges from 10 to 50% for curettage with Medical Center). We aim to find distinctive imaging features for malignant transformation in GCTB on different mo- local adjuvants and 5% for wide resection [5–9]. Medical treatment for GCTB includes denosumab, a monoclonal dalities. In addition, we will assess the duration of deno- sumab treatment as a possible risk factor for secondary antibody which binds to RANKL and inhibits bone de- struction and osteolysis [3]. Histologically, denosumab in- malignant transformation and review lag time to the de- duces intralesional deposition of bone with a strong velopment of malignancy. depletion of giant cells. Early after treatment, the cellularity is high, with haphazard bone deposition, while after pro- 2. Methods longed therapy cellularity decreases while the new bone is deposited as broad, rounded cords or long, curvilinear arrays (e LUMC pathology database was searched for the diag- [10]. (us, the morphology after treatment is variable and nosis of GCTB with atypical features and mGCTB using can resemble osteosarcoma, though significant nuclear diagnostic codes. 17 potential cases were found and a review atypia, mitotic activity, and infiltration of preexisting bone of cases was performed both radiologically (by two MSK are absent [10]. oncology radiologists, KvL and ANC) and histologically (by Neo-adjuvant treatment with denosumab is relevant in two bone and soft tissue tumor pathologists, AHGC and cases where surgical resection may result in severe morbidity JVMGB). A clinical oncologist (HG) reviewed the medical (such as joint reconstruction or amputation) and a short- history involving denosumab as to obtain the duration of term treatment of three months is given to facilitate surgery treatment and time interval before diagnosis of malignant and decrease tumor pain [11]. Long-term denosumab may transformation (lag time). An orthopaedic surgeon (LvdH) be used as a primary treatment in patients who have an reviewed the medical charts for symptoms of pain or new unresectable tumor (often in the spine or sacrum). Deno- functional impairment preceding malignant transformation. sumab treatment has been shown to limit tumor progres- All samples were handled according to the ethical guidelines sion, reduce tumor size, increase bone formation and bone described in the “Code for Proper Secondary Use of Human mineral density, reduce pain, and improve functional status Tissue in the Netherlands,” as approved by the Leiden [5, 6, 12, 13]. University Medical Centre ethical board. Informed consent Malignancy in GCTB (mGCTB) is categorized by the was obtained from the subjects (through the Dutch Bone WHO classification as primary (a nodule of highly pleo- Tumor Committee and LUMC biobank) or, in case they morphic, neoplastic mononuclear cells occurring concom- were deceased, the next of kin gave consent. Molecular itantly with an otherwise conventional GCTB) or secondary analysis (H3G34W immuno or targeted NGS) was per- (occurring after treatment often involving radiotherapy) [2]. formed on biopsy samples and resection specimens before In secondary malignant transformation, the conventional and after malignant transformation depending on the GCTB may or may not be detectable [2, 14–16]. (e ma- availability of samples. lignant component does not have specific histological fea- As for radiological assessment of the cases, conventional tures and may be either an undifferentiated sarcoma or an images (X-ray), computed tomography (CT), F-FDG- osteosarcoma with telangiectatic or osteoblastic features positron emission tomography-CT (PET-CT) and magnetic [2, 8, 16]. Tahir et al. recently reviewed the literature on resonance imaging (MRI) were taken into account mGCTB and found that in secondary mGCTB, morpho- depending on the availability in our LUMC PACS (some logical subtypes were osteosarcoma in 58%, fibrosarcoma in patients were referred from elsewhere). Radiological features 32%, and undifferentiated pleomorphic sarcoma in 10% of malignant GCTB were described as we aimed to find (N � 84 cases) [17]. In mGCTB, the H3G34W mutation can distinctive imaging features for malignant transformation. be either retained or absent [2, 18–20]. Strong expression of All cases were discussed during multidisciplinary consensus p53 has been described in a subset of secondary mGCTB [2]. meetings. (ere is an ongoing debate about denosumab being a Cases were categorized as primary or secondary mGCTB risk factor for mGCTB. (e largest prospective clinical trial according to the WHO 2020 criteria: primary mGCTB is to date (n � 532) reported 1% of confirmed sarcomatous composed of a nodule of sarcomatous growth juxtaposed to transformation in GCTB patients on denosumab [13]. zones of conventional GCTB, and secondary mGCTB is a Several cases of sarcomatous transformation in recurrent sarcomatous growth that occurs at the site of a previously GCTB have been described, respectively, in the tibia with documented benign GCTB after treatment [2, 14, 22]. transformation into a high-grade pleomorphic sarcoma after Subgroups of secondary malignant GCTB were made based Sarcoma 3 stable or increased size of the soft tissue component on CTor on risk factors such as surgery, radiotherapy, and denosu- mab or a combination of two or more of these risk factors. MRI while on denosumab treatment. (e criteria used to distinguish mGCTB from conventional denosumab related treatment changes in GCTB included 3.1. Case 1. An X-ray at presentation showed an osteolytic nuclear atypia (especially hyperchromasia), high mitotic tumor with cortical destruction in the left iliac wing activity, atypical mitotic figures, extensive necrosis, and (Figure 1(a)). Baseline MRI axial T2 TSE weighted sequence infiltration of preexisting bone [2, 10]. Of note, we did not showed an expansive tumor in the left posterior aspect of the include cases of other bone sarcomas harbouring a H3G34W iliac wing with central necrosis and a peripheral thick low mutation into this case series, if they were histologically not signal intensity rim (Figure 1(b)). T1 SPIR after contrast related to GCTB, as it is at present unclear whether these showed enhancement mainly of the tumor rim and, in represent malignant GCTB [2]. addition enhancement of the adjacent bone marrow edema in the sacrum and ilium (Figure 1(c)). (e diagnosis of 3. Results conventional GCTB (H3G34W positive) was made after CT guided biopsy (Figures 1(f) and 1(g)), followed by the start Of the 17 potential cases, six were defined as mGCTB after of denosumab therapy. CT scans performed 5 and 8 months pathology review. An overview of the cases is given in Ta- after starting denosumab treatment showed no decrease in ble 1. (e mean age was 42 years (range 27–55) at the time of tumor size and no increase tumor density (Figures 1(d) and GCTB diagnosis. Five out of six patients (83%) were female. 1(e)). Furthermore, no thick rim of neocortex was formed (e tumor sites were distal femur (n � 2), tarsal navicular and multiple foci of cortical disruption persisted during (n � 1), ilium (n � 1), sacrum (n � 1), and lumbar spine treatment. Based on these worrisome radiological features, a (n � 1). resection was performed and the diagnosis of mGCTB was All cases were secondary mGCTB. Before the diagnosis confirmed. Histology at the time of resection showed of mGCTB was confirmed, 4 out of 6 patients reported an atypical cells with enlarged hyperchromatic nuclei, scattered increase in pain and functional impairment; 2 underwent monstrous tumor cells, atypical mitotic figures, and depo- their routinely scheduled follow-up imaging and in 2 pa- sition of tumor osteoid. (e stromal cells remained positive tients imaging was performed earlier than their regularly for H3G34W (Figures 1(h) and 1(i)). planned outpatient visits due to clinical complaints. At the time of mGCTB diagnosis, two patients were treated with denosumab only, two with denosumab and surgery, one 3.2. Case 3. An X-ray at the time of initial presentation with multiple curettages due to recurrence followed by ra- showed an osteolytic lesion in the distal femur meta- diotherapy, and one case was treated with surgery only. In all epiphysis complicated by an intra-articular pathological four denosumab treated patients, the mean lag time between fracture, for which external fixation was performed the start of denosumab treatment and malignant transfor- (Figure 2(a)). Cortical scalloping was present on CT and no matrix formation was noted (Figures 2(b) and 2(c)). MRI mation was 7 months (range 2–11 months). In the subgroup treated with denosumab only (n � 2), the mean lag time was showed a high signal intensity on T1-weighted images, partly due to hemorrhage after the fracture. T2-weighted images 6.5 months (range 2–11 months). In the two patients treated with both surgery and denosumab, the mean lag time was 7.5 showed a heterogeneous mass with mostly high signal in- months (range 5–10 months). (e case with radiation-as- tensity. A posterior soft tissue mass was found and intra- sociated malignant GCTB had a lag time of 13 years. (e articular extension of the tumor was present anterolaterally patient treated with surgery only had a latency period of 9 (MR images not shown, due to poor quality). Biopsy con- months between surgery and mGCTB diagnosis. (e clinical firmed the diagnosis of conventional GCTB (Figures 2(d)– outcome is shown in Table 1. 2(f)). (e patient was treated with curettage and cement and Only two out of six cases showed imaging findings at the the fracture was fixated with plate osteosynthesis. On a primary tumor location suspicious of malignant transfor- follow-up CT of the knee performed 1 year later, new osteolysis was present medial of the cement with cortex mation, even when reviewed retrospectively with histo- pathological guidance. Case 2 presented with a new tumor destruction, interpreted as a local recurrence (Figure 3(a)). (e patient was therefore started on denosumab treatment. location, i.e., a metastasis elsewhere in the spine. Imaging features suspicious of malignant transformation were noted After 10 months on denosumab, the CT showed progression in cases 1 and 3. (ese cases are described in more detail into a large medial soft tissue mass which was covered by below (and in Table 2). In two other cases, mGCTB was irregular neocortex. (e bone density of the endomedullary presented with findings similar to a local recurrence (cases 4 component of the local recurrence was increased most likely and 6). A mixed response to denosumab was noted in case 5 due to denosumab. However, within the increased soft tissue that showed bone deposition and neocortex formation mass there was new osteoid matrix formation proximally, suspicious of malignant transformation in GCTB following denosumab on CT, however no decrease in tumor size. Imaging characteristics pointing towards malignant (Figure 3(b)). En bloc resection was performed, the mac- roscopic resection specimen (Figure 3(c)) and preoperative transformation are grouped by modality in Table 3. For the musculoskeletal radiologist, key findings pointing towards sagittal CT reformatted image (Figure 3(d)) showed corre- sponding endomedullary fibro-osseous matrix formation malignant transformation are: absence of fibro-osseous matrix formation and neocortex formation on CT, and (asterisk) with osteoid deposition in a posteromedial new 4 Sarcoma Table 1: Overview of mGCTB cases: histology and therapy before malignant transformation. Time first Previous surgery Interval start Primary or Sex Age at History of Histology at the Previous Case Tumor Histology at diagnosis to before malignant Denosumab Duration of denosumab to secondary (M/ diagnosis malignancy time of radiotherapy Clinical outcome nr site biopsy malignant transformation Y/N denosumab malignant malignant F) (years) Y/N transformation Y/N transformation Y/N transformation transformation Died 7 months High-grade Secondary, after malignant Y, breast Left GCTB, 1 F 54 osteosarcoma, 12 months N N Y 7 months 11 months denosumab diagnosis (cause cancer ilium H3G34W+ H3G34W+ associated unknown), lost to follow-up Died 12 months 92 months (from after malignant first diagnosis to Secondary, diagnosis due to Metastatic lesion in development of GCTB, denosumab and multiple vertebral 2 F 35 N L2 (2: Sarcoma metastasis with Y Y Y 5 months 5 months H3G34W+ surgery metastases with NOS, H3G34W+ malignant associated cervicothoracic transformation in myelum (2) compression Died 44 months Secondary, High-grade after malignant Left GCTB, Y (curettage with denosumab and 3 F 55 N osteosarcoma, 23 months N Y 10 months 10 months diagnosis due to femur H3G34W+ cement) surgery H3G34W− pulmonary associated metastases Recurrence with malignancy in Y (curettage, Left GCTB, GCTB (also areas liquid nitrogen Secondary, 4 F 37 N tarsal 12 months N N NA NA NED H3G34W + with conventional and cancellous postsurgery navicular GCTB). H3G34W bone graft) missing Highly suspicious 2 months, Secondary, GCTB, for progression to 5 M 45 N Sacrum 2 months N N Y neoadjuvant 2 months denosumab NED H3G34W + malignant GCTB, to surgery associated H3G34W+ Resection: low- grade sarcoma, radiation associated. H3G34W+ Amputation (2 yrs later): high-grade sarcoma, H3G34W+ En bloc resection GCTB, Y (multiple Secondary, of soft tissue H3G34W curettages; liquid radiotherapy Residual metastasis Right recurrence in the 6 F 27 N missing 21 years nitrogen, Y N NA NA associated present in L4, femur stump (4 yrs later): (before cancellous bone (interval 13 otherwise NED high-grade 2000) graft and cement) years) sarcoma (possibly radiation associated), however H3G34W− Intralesional resection of solitary L4 sarcoma metastasis (4.5 yrs later): H3G34W+ Sarcoma 5 Table 2: Radiological characteristics of GCTB before and after malignant transformation. Case X ray/(PET) CT at time of Tumor site MRI at time of diagnosis X ray/CT at time of transformation MRI at time of transformation nr diagnosis (ick walled lesion with central CT after 5 and 8 months of denosumab: X-ray: lytic lesion with cortex 1 Left ilium necrosis, rim enhancement, and absent fibro-osseous matrix and neocortex Not performed destruction adjacent bone marrow edema formation. Unchanged tumor size T2 hyperintense mass in (2 with large soft CT: recurrence with right paravertebral soft X-ray: lytic lesion with cortex High T2 signal intensity with some foci tissue component, epidural extension and 2 L2 tissue mass at (2. No osteolysis of the destruction and soft tissue mass of low signal myelum compression, homogeneous vertebral body enhancement postcontrast X-ray: lytic lesion with CT of the local recurrence after denosumab Lesion with high SI on T1 (partly due to pathological fracture in the showed new cortex destruction with a soft hemorrhage after fracture) and T2, 3 Left femur meta-epiphysis. CT showed tissue mass, endomedullary irregular Not performed heterogeneous. Rim enhancement after cortical scalloping and focal sclerosis and new osteoid matrix formation contrast cortex destruction proximally MRI 3.5 months postcurettage: recurrence around cancellous bone graft, higher signal intensity lesion on T2. Extension into the Lytic lesion with cortex destruction. talocalcaneal joint space. X-ray: lytic lesion in the tarsal Left tarsal Iso-intense on T1, heterogeneous low X-ray: resorption of the cancellous bone MRI 7.5 months postcurettage: increase of 4 navicular bone without cortex navicular signal intensity on T2. Extension into graft the recurrence. Extending into tarsalia and destruction lateral cuneiform and cuboid bone calcaneum. High T2 signal (marked increase of signal intensity compared to initial MRI at presentation). Multilobulated appearance. Bone marrow edema+ Lytic lesion with destruction of cortex, CT: foci of ossification in the presacral large presacral soft tissue mass. Central component (on denosumab). Neocortex max 5 Sacrum (PET)-CT: osteolysis. SUV 21 Not performed cystic/necrotic component high on T2, formation+ not enhancing. Low foci on T2 No decrease in tumor size MRI at the time of first malignant transformation: multifocal recurrence X-ray showed a well demarcated around cement/cancellous bone graft in Right lytic lesion in the lateral femoral CT: osteolysis adjacent to the cement in the 6 Not performed femur and tibia femur condyle with a pathological femur and cortex destruction MRI 2 yrs later: large heterogeneous soft fracture tissue mass in the popliteal fossa with fast enhancement after contrast 6 Sarcoma Table 3: Overview of radiological characteristics suggestive of GCTB malignant transformation, compared to baseline GCTB diagnosis. Imaging modality X-ray (PET) CT MRI ∗ ∗ Absent fibro-osseous matrix formation No increased density on CT (HU) [23] Absent neocortex formation max ∗ ∗ Absent neocortex formation No decrease in SUV [5] ∗ ∗ Stable size or increase in size of the soft tissue component Stable size or increase in size of the soft tissue component New cortex destruction New cortex destruction New cortex destruction New soft tissue mass New soft tissue mass Metastasis (new tumor localisation) Metastasis (new tumor localisation) Specific to denosumab treatment. Sarcoma 7 (a) (b) (c) (d) (e) (f) (g) (h) (i) Figure 1: Case 1, a 54-year-old female with a GCTB in the left ilium. (a) X-ray at presentation shows an osteolytic tumor with cortical destruction (arrowheads) cranially in the left iliac wing, adjacent to the sacroiliac joint. (b) MRI at the time of diagnosis; axial T2 TSE shows an expansive tumor in the left posterior aspect of the ilium with central necrosis and a peripheral thick low signal intensity rim. (c) MRI at the time of diagnosis; T1 SPIR postgadolinium (Gd) shows heterogeneous enhancement, mainly of the tumor rim and adjacent bone marrow edema in the sacrum (arrow) and ilium. (d) Axial unenhanced CT images; 5 months after starting denosumab treatment and (e) 8 months after starting denosumab treatment. Both scans showed no decrease in size and no matrix formation centrally. No thick rim of neocortex was formed. (f) Histology; morphology of first biopsy confirmed the diagnosis of conventional GCTB: mononuclear stromal cells intermixed with osteoclast-like giant cells. (e mononuclear cells have slightly enlarged nuclei and predominate over the giant cells, but since overt nuclear atypia and hyperchromasia and atypical mitoses are absent the diagnosis is still compatible with conventional giant cell tumor of bone. In the background reactive lymphocytes and some sclerosis. (g) Immunohistochemistry of the biopsy at the time of presentation: mononuclear stromal cells positive for H3G34W (scale bar 50μm). (h) Histology of resection after denosumab treatment showed malignant GCTB: atypical cells with enlarged hyperchromatic nuclei, scattered monstrous tumor cells, and atypical mitotic figures with matrix deposition suggestive of tumor osteoid. (i) Immunohistochemistry at the time of resection after denosumab treatment showed atypical stromal cells positive for H3G34W. 8 Sarcoma (a) (b) (c) (d) (e) (f) Figure 2: Case 3, a 55-year-old female with a pathological fracture of the femur with underlying GCTB. (a) X-ray at the time of diagnosis showed a pathological fracture through a well-defined osteolytic lesion with a sclerotic margin in the distal femur meta- and epiphysis, initially treated by external fixation. (b) Coronal and (c) sagittal CT images at the time of diagnosis showed the pathological fracture extending through the anterior and posterior cortices (arrows) and no internal matrix. (d) Morphology at the time of curettage shows many mononuclear stromal cells intermixed with large osteoclast-like giant cells without atypical morphological features. (e) At the time of curettage; areas with reactive woven bone with typical osteoblast lining are seen, which may be due to the clinical fracture. (f) At the time of curettage; heterogeneous positive H3G34W staining in stromal cells. increased size of the soft tissue component on CT or MRI mass lesion. Histology at the time of en bloc resection revealed a sarcomatous appearing cellular spindle cell while on denosumab treatment. proliferation with areas of tumor necrosis and the formation Regardless of the association with denosumab, findings of tumor osteoid. Histological features were in keeping with that should alert the radiologist to think of malignant a high-grade osteosarcoma (Figures 3(e) and 3(f)). (e transformation in GCTB are areas of new cortex destruction, endomedullary osteoid deposition was more regular in a new soft tissue mass, and new tumor localisations i.e., appearance and the criteria for sarcomatous progression (nonpulmonary) metastases. were not met. (erefore this fitted with denosumab induced X-ray findings suspicious for secondary mGCTB were changes. described previously, including less distinct margins and a soft tissue mass (present in 75% of cases), and cortical breakthrough (in 83% of cases) [14] and confirmed by 4. Discussion Domovitov and Healey in 2010 [15]. Grading a tumor as Six cases of secondary mGCTB are reported containing Campanacci grade III on X-ray does not differentiate be- imaging features suspicious of sarcomatous transformation tween aggressive conventional versus mGCTB [17, 24]. In in three cases. One case showed a mixed response on both studies no CT or MRI features were described, and denosumab treatment, and the remaining two showed denosumab treatment was not taken into account [14, 15]. findings in keeping with a local recurrence. Key imaging Secondary mGCTB may present with two distinct tumor findings suspicious of malignant transformation related to components on CT: a previous case-report showed a low- denosumab therapy are the absence of fibro-osseous matrix density component which histologically corresponded to a formation and neocortex formation on CT, and stable or high-grade sarcoma and a high-density component which Sarcoma 9 (a) (b) (c) (d) (e) (f) Figure 3: Case 3, same case as in Figure 2; local recurrence occurred 1 year after curettage, followed by denosumab treatment. After en bloc resection, the diagnosis of malignant GCTB was made. (a) Coronal CT image performed for follow-up approximately 1 year after surgery showed osteolysis along the medial bone-cement interface (arrows) in keeping with local recurrence. Denosumab treatment was started after this scan. (b) Coronal CT image after 10 months of denosumab therapy showed increased density in the osteolytic area of recurrence due to formation of fibro-osseous tissue (vertical arrow at the medial femoral condyle), the tumor expanded further into the soft tissues with an irregular margin (horizontal arrows). In addition, proximal to the area of local recurrence there was a newly formed component of osteoid matrix (dotted arrows), suspicious for progression to osteosarcoma. (c) Photograph of tumor macroscopy (sagittal section) after en bloc resection shows the cementum from the previous surgery, surrounded by tumor tissue extending into the soft tissue. (d) Sagittal CT reformatted after the macroscopy section (Figure 3(c)) shows endomedullary cement and holes due to previous screw tracts, surrounded by denosumab changes (asterisk). Posterior soft tissue mass is noted with osteoid matrix formation suspicious for an osteosarcoma (dotted arrows). (e) Histology at the time of resection; low power view displaying highly cellular spindle cell proliferation with areas of tumor necrosis (left) and the formation of tumor osteoid (right). Scale bar of 50 μm. (f) Tumor osteoid in high-power field fitting with the histological features of an osteosarcoma. Scale bar 50μm. 10 Sarcoma misclassification in our cases. Furthermore, in case 3, no corresponded to areas of conventional GCTB with changes related to denosumab treatment. (e lag time was 13 months biopsy was performed at the time of local recurrence. Denosumab treatment was started and mGCTB was proven [21]. Our case 3 differed in that the component with sar- comatous transformation was not osteolytic but showed after 10 months of medical treatment at the time of re- osteoid matrix formation, adjacent to the expected deno- section. (erefore, we cannot prove an association with sumab changes in the conventional GCTB component. denosumab in this case of secondary mGCTB. Tsukamoto et al. presented a case of secondary mGCTB A limitation of this case series is that imaging was done with a lag time of six months after the start of denosumab in multiple centers and not performed with standardized therapy. A CT scan performed at that time revealed en- MRI bone tumor scanning protocols including diffusion weighted imaging and dynamic contrast enhanced se- largement of a poorly defined osteoblastic mass, and a bi- opsy-confirmed high-grade sarcoma [18]. quences. Unfortunately, none of the cases in our series had MR perfusion imaging done on multiple time points. We did In summary, growth instead of a decrease in the size of the tumor during denosumab treatment is a sign pointing not have multiple timepoints of PET-CTs available to assess max SUV towards malignant transformation and this can present over time on denosumab treatment. It is known that max either as an osteolytic or osteoblastic lesion. absent decrease in SUV on PET-CT is suspicious for (e mean lag time between the start of denosumab malignant transformation of GCTB [5, 23]. treatment and malignant transformation was 7 months (range 2–11 months). (is is in accordance with previously 5. Conclusions published cases, with a lag time ranging from 6 to 13 months In only 50% of cases, radiological findings were indicative of [17, 18, 22]. In our case series, there was no clinically relevant malignant transformation, even when assessed retrospec- difference in mean lag time between patients treated with tively together with histopathology. In five out of six patients denosumab only versus patients treated with both surgery presented in this case series, malignant transformation and denosumab. (secondary mGCTB) occurred within the first year after the (e one case with surgery as the only risk factor for start of denosumab treatment or surgery. (ese findings malignant transformation had undergone curettage with stress the importance of close clinical and imaging follow-up bone grafting and the latency time to mGCTB was 9 months. in the first months after denosumab therapy for GCTB, as A hypothesis to explain surgery as the only risk factor for mGCTB tends to have rapid aggressive behavior, similar to mGCTB may be the application of (cancellous) bone other high-grade sarcomas. (e definitive diagnosis is based grafting, as the borders of the dead bone could form the on histology as radiology is not sufficient. nidus of a malignant tumor. (is mechanism has been (e medical oncologist and the radiologist play an proposed for sarcomas related to bone infarction [14, 25]. important role in the surveillance of these complex cases. On (e case with radiation-associated mGCTB had a lag denosumab treatment, the absence of the expected pain time of 13 years, in agreement with the literature, where relief in the first months after starting treatment or even new radiotherapy-associated mGCTB was shown to have a or increased pain are concerning and warrant further or new longer lag time than denosumab-associated sarcomatous diagnostic evaluation of the tumor [13, 28]. In addition to transformation, on average, eight years [14, 16, 26, 27]. that, if the known imaging response to denosumab treat- In our case series five out of six cases were women, the ment does not occur after 8–12 weeks, we recommend short greater percentage of women affected with secondary interval follow-up (for example, repeat CTafter 4 weeks) and mGCTB is in accordance with previous publications [15, 26], in case of no response, biopsy needs to be repeated. but a male predominance in secondary mGCTB has been found by others [14, 24]. Data Availability In four out of six cases, the H3G34W mutation was present at the time of diagnosis of secondary mGCTB. In one (e radiological and histopathological data used to sup- case the mutation was lost (case 3), and there was one case port the findings of this study are included within the with missing data at the time of malignant transformation article. (case 4). As the H3G34W mutation may be retained or lost in secondary mGCTB [20], it is key to re-evaluate the tissue Conflicts of Interest from the time of diagnosis of conventional GCTB to prevent misclassification. All authors declare no conflicts of interest. (e misdiagnosis of primary mGCTB as conventional GCTB is an important phenomenon, which has been Authors’ Contributions addressed in several recent publications [24, 28]. (erefore, in our case series on secondary mGCTB, two experienced KvL performed the concept and design of the study, drafted bone tumor pathologists reviewed all available biopsies, the manuscript, collected, and reviewed all radiological data. curettages, and resection specimens to verify the primary AHGC performed the histopathology and molecular pa- presentation of conventional GCTB and confirm the diag- thology data review, revision, and approval of the manu- nosis in all six cases. Nevertheless, we cannot completely rule script. ANC reviewed radiological data, revision, and out sampling error in cases only biopsy material was present approval of the manuscript. LvdH and MAJvdS obtained at the time of first diagnosis, which may have been a cause of orthopaedic clinical data, revision, and approval of the Sarcoma 11 in denosumab treatment of giant cell tumour of bone,” BMJ manuscript. 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Malignant Transformation of Giant Cell Tumor of Bone and the Association with Denosumab Treatment: A Radiology and Pathology Perspective

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Hindawi Sarcoma Volume 2022, Article ID 3425221, 11 pages https://doi.org/10.1155/2022/3425221 Research Article Malignant Transformation of Giant Cell Tumor of Bone and the Association with Denosumab Treatment: A Radiology and Pathology Perspective 1 2,3 1 4 K. van Langevelde , A. H. G. Cleven , A. Navas Cañete , L. van der Heijden , 4 5 2 M. A. J. van de Sande , H. Gelderblom , and J. V. M. G. Bovee ´ Department of Radiology, Leiden University Medical Center, Leiden, Netherlands Department of Pathology, Leiden University Medical Center, Leiden, Netherlands Department of Pathology, University Medical Center Groningen, Groningen, Netherlands Department of Orthopedics, Leiden University Medical Center, Leiden, Netherlands Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands Correspondence should be addressed to K. van Langevelde; k.van_langevelde@lumc.nl Received 18 March 2022; Accepted 25 May 2022; Published 17 June 2022 Academic Editor: Kanya Honoki Copyright © 2022 K. van Langevelde et al. �is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objective. Malignancy in giant cell tumor of bone (mGCTB) is categorized as primary (concomitantly with conventional GCTB) or secondary (after radiotherapy or other treatment). Denosumab therapy has been suggested to play a role in the etiology of secondary mGCTB. In this case series from a tertiary referral sarcoma center, we aimed to ‰nd distinctive features for malignant transformation in GCTB on diŠerent imaging modalities. Furthermore, we assessed the duration of denosumab treatment and lag time to the development of malignancy. Methods. From a histopathology database search, 6 patients were pathologically con‰rmed as having initial conventional GCTB and subsequently with secondary mGCTB. Results. At the time of mGCTB diagnosis, 2 cases were treated with denosumab only, 2 with denosumab and surgery, 1 with multiple curettages and radiotherapy, and 1 with surgery only. In the 4 denosumab treated patients, the mean lag time to malignant transformation was 7 months (range 2–11 months). Imaging ‰ndings suspicious of malignant transformation related to denosumab therapy are the absence of ‰bro- osseous matrix formation and absent neocortex formation on CT, and stable or even increased size of the soft tissue component. Conclusion. In 4 patients treated with denosumab, secondary mGCTB occurred within the ‰rst year after initiation of treatment. Radiotherapy-associated mGCTB has a longer lag time than denosumab-associated mGCTB. Close clinical and imaging follow-up during the ‰rst months of denosumab therapy is key, as mGCTB tends to have rapid aggressive behavior, similar to other high- grade sarcomas. Nonresponders should be (re) evaluated for their primary diagnosis of conventional GCTB. types: neoplastic mononuclear stromal cells, macrophages, 1. Introduction and osteoclast-like giant cells. �e neoplastic mononuclear Giant cell tumor of bone (GCTB) typically occurs in young stromal cells express a receptor activator of nuclear factor adults between 20 and 40 years of age after closure of the kappa-B ligand (RANKL) which binds with the RANK re- physis. GCTB arises from the epi-metaphysis and extends up ceptor on osteoclast precursors. Via the RANK-RANKL to the subchondral bone plate [1]. �e 2020 WHO classi- signaling pathway these cells induce osteoclast formation ‰cation of soft tissue and bone tumors [2] de‰nes GCTB as a which gives the typical osteolytic appearance to the tumor locally aggressive tumor that rarely metastasizes. A further [3]. �e incidence of GCTB is 1.66 per million inhabitants division is made into two subtypes: conventional and ma- per year, based on a nationwide pathology database study in lignant GCTB. Conventional GCTB contains three cell the Netherlands. During the 5-year study period, from 2 Sarcoma 13 months on denosumab treatment [21], and in the ischium January 2009 to December 2013, a total of 138 new cases of GCTB were found, with only 1 case of malignant GCTB [1]. with transformation into a high-grade osteosarcoma after 6 months on treatment [18]. However, whether sarcomatous H3F3A gene mutations are detected in at least 95% of giant cell tumors, and 90% of these mutations are repre- transformation in (recurrent) GCTB is a causal or coinci- sented by the H3.3 pGly34Trp mutation [2]. H3.3 pGly34Trp dental phenomenon with regards to the use of denosumab is (H3G34W) immunohistochemistry is a reliable surrogate unclear for these cases, and as yet no biological hypothesis marker for molecular analysis [4]. Within the context of exists that explains the association between denosumab bone tumors, this marker is highly specific for GCTB. treatment and malignant transformation. (e primary treatment for GCTB is surgical excision. In this case series, we aim to give an overview of mGCTB patients from our tertiary referral center (Leiden University (e rate of local recurrence depends on the type of surgery performed and ranges from 10 to 50% for curettage with Medical Center). We aim to find distinctive imaging features for malignant transformation in GCTB on different mo- local adjuvants and 5% for wide resection [5–9]. Medical treatment for GCTB includes denosumab, a monoclonal dalities. In addition, we will assess the duration of deno- sumab treatment as a possible risk factor for secondary antibody which binds to RANKL and inhibits bone de- struction and osteolysis [3]. Histologically, denosumab in- malignant transformation and review lag time to the de- duces intralesional deposition of bone with a strong velopment of malignancy. depletion of giant cells. Early after treatment, the cellularity is high, with haphazard bone deposition, while after pro- 2. Methods longed therapy cellularity decreases while the new bone is deposited as broad, rounded cords or long, curvilinear arrays (e LUMC pathology database was searched for the diag- [10]. (us, the morphology after treatment is variable and nosis of GCTB with atypical features and mGCTB using can resemble osteosarcoma, though significant nuclear diagnostic codes. 17 potential cases were found and a review atypia, mitotic activity, and infiltration of preexisting bone of cases was performed both radiologically (by two MSK are absent [10]. oncology radiologists, KvL and ANC) and histologically (by Neo-adjuvant treatment with denosumab is relevant in two bone and soft tissue tumor pathologists, AHGC and cases where surgical resection may result in severe morbidity JVMGB). A clinical oncologist (HG) reviewed the medical (such as joint reconstruction or amputation) and a short- history involving denosumab as to obtain the duration of term treatment of three months is given to facilitate surgery treatment and time interval before diagnosis of malignant and decrease tumor pain [11]. Long-term denosumab may transformation (lag time). An orthopaedic surgeon (LvdH) be used as a primary treatment in patients who have an reviewed the medical charts for symptoms of pain or new unresectable tumor (often in the spine or sacrum). Deno- functional impairment preceding malignant transformation. sumab treatment has been shown to limit tumor progres- All samples were handled according to the ethical guidelines sion, reduce tumor size, increase bone formation and bone described in the “Code for Proper Secondary Use of Human mineral density, reduce pain, and improve functional status Tissue in the Netherlands,” as approved by the Leiden [5, 6, 12, 13]. University Medical Centre ethical board. Informed consent Malignancy in GCTB (mGCTB) is categorized by the was obtained from the subjects (through the Dutch Bone WHO classification as primary (a nodule of highly pleo- Tumor Committee and LUMC biobank) or, in case they morphic, neoplastic mononuclear cells occurring concom- were deceased, the next of kin gave consent. Molecular itantly with an otherwise conventional GCTB) or secondary analysis (H3G34W immuno or targeted NGS) was per- (occurring after treatment often involving radiotherapy) [2]. formed on biopsy samples and resection specimens before In secondary malignant transformation, the conventional and after malignant transformation depending on the GCTB may or may not be detectable [2, 14–16]. (e ma- availability of samples. lignant component does not have specific histological fea- As for radiological assessment of the cases, conventional tures and may be either an undifferentiated sarcoma or an images (X-ray), computed tomography (CT), F-FDG- osteosarcoma with telangiectatic or osteoblastic features positron emission tomography-CT (PET-CT) and magnetic [2, 8, 16]. Tahir et al. recently reviewed the literature on resonance imaging (MRI) were taken into account mGCTB and found that in secondary mGCTB, morpho- depending on the availability in our LUMC PACS (some logical subtypes were osteosarcoma in 58%, fibrosarcoma in patients were referred from elsewhere). Radiological features 32%, and undifferentiated pleomorphic sarcoma in 10% of malignant GCTB were described as we aimed to find (N � 84 cases) [17]. In mGCTB, the H3G34W mutation can distinctive imaging features for malignant transformation. be either retained or absent [2, 18–20]. Strong expression of All cases were discussed during multidisciplinary consensus p53 has been described in a subset of secondary mGCTB [2]. meetings. (ere is an ongoing debate about denosumab being a Cases were categorized as primary or secondary mGCTB risk factor for mGCTB. (e largest prospective clinical trial according to the WHO 2020 criteria: primary mGCTB is to date (n � 532) reported 1% of confirmed sarcomatous composed of a nodule of sarcomatous growth juxtaposed to transformation in GCTB patients on denosumab [13]. zones of conventional GCTB, and secondary mGCTB is a Several cases of sarcomatous transformation in recurrent sarcomatous growth that occurs at the site of a previously GCTB have been described, respectively, in the tibia with documented benign GCTB after treatment [2, 14, 22]. transformation into a high-grade pleomorphic sarcoma after Subgroups of secondary malignant GCTB were made based Sarcoma 3 stable or increased size of the soft tissue component on CTor on risk factors such as surgery, radiotherapy, and denosu- mab or a combination of two or more of these risk factors. MRI while on denosumab treatment. (e criteria used to distinguish mGCTB from conventional denosumab related treatment changes in GCTB included 3.1. Case 1. An X-ray at presentation showed an osteolytic nuclear atypia (especially hyperchromasia), high mitotic tumor with cortical destruction in the left iliac wing activity, atypical mitotic figures, extensive necrosis, and (Figure 1(a)). Baseline MRI axial T2 TSE weighted sequence infiltration of preexisting bone [2, 10]. Of note, we did not showed an expansive tumor in the left posterior aspect of the include cases of other bone sarcomas harbouring a H3G34W iliac wing with central necrosis and a peripheral thick low mutation into this case series, if they were histologically not signal intensity rim (Figure 1(b)). T1 SPIR after contrast related to GCTB, as it is at present unclear whether these showed enhancement mainly of the tumor rim and, in represent malignant GCTB [2]. addition enhancement of the adjacent bone marrow edema in the sacrum and ilium (Figure 1(c)). (e diagnosis of 3. Results conventional GCTB (H3G34W positive) was made after CT guided biopsy (Figures 1(f) and 1(g)), followed by the start Of the 17 potential cases, six were defined as mGCTB after of denosumab therapy. CT scans performed 5 and 8 months pathology review. An overview of the cases is given in Ta- after starting denosumab treatment showed no decrease in ble 1. (e mean age was 42 years (range 27–55) at the time of tumor size and no increase tumor density (Figures 1(d) and GCTB diagnosis. Five out of six patients (83%) were female. 1(e)). Furthermore, no thick rim of neocortex was formed (e tumor sites were distal femur (n � 2), tarsal navicular and multiple foci of cortical disruption persisted during (n � 1), ilium (n � 1), sacrum (n � 1), and lumbar spine treatment. Based on these worrisome radiological features, a (n � 1). resection was performed and the diagnosis of mGCTB was All cases were secondary mGCTB. Before the diagnosis confirmed. Histology at the time of resection showed of mGCTB was confirmed, 4 out of 6 patients reported an atypical cells with enlarged hyperchromatic nuclei, scattered increase in pain and functional impairment; 2 underwent monstrous tumor cells, atypical mitotic figures, and depo- their routinely scheduled follow-up imaging and in 2 pa- sition of tumor osteoid. (e stromal cells remained positive tients imaging was performed earlier than their regularly for H3G34W (Figures 1(h) and 1(i)). planned outpatient visits due to clinical complaints. At the time of mGCTB diagnosis, two patients were treated with denosumab only, two with denosumab and surgery, one 3.2. Case 3. An X-ray at the time of initial presentation with multiple curettages due to recurrence followed by ra- showed an osteolytic lesion in the distal femur meta- diotherapy, and one case was treated with surgery only. In all epiphysis complicated by an intra-articular pathological four denosumab treated patients, the mean lag time between fracture, for which external fixation was performed the start of denosumab treatment and malignant transfor- (Figure 2(a)). Cortical scalloping was present on CT and no matrix formation was noted (Figures 2(b) and 2(c)). MRI mation was 7 months (range 2–11 months). In the subgroup treated with denosumab only (n � 2), the mean lag time was showed a high signal intensity on T1-weighted images, partly due to hemorrhage after the fracture. T2-weighted images 6.5 months (range 2–11 months). In the two patients treated with both surgery and denosumab, the mean lag time was 7.5 showed a heterogeneous mass with mostly high signal in- months (range 5–10 months). (e case with radiation-as- tensity. A posterior soft tissue mass was found and intra- sociated malignant GCTB had a lag time of 13 years. (e articular extension of the tumor was present anterolaterally patient treated with surgery only had a latency period of 9 (MR images not shown, due to poor quality). Biopsy con- months between surgery and mGCTB diagnosis. (e clinical firmed the diagnosis of conventional GCTB (Figures 2(d)– outcome is shown in Table 1. 2(f)). (e patient was treated with curettage and cement and Only two out of six cases showed imaging findings at the the fracture was fixated with plate osteosynthesis. On a primary tumor location suspicious of malignant transfor- follow-up CT of the knee performed 1 year later, new osteolysis was present medial of the cement with cortex mation, even when reviewed retrospectively with histo- pathological guidance. Case 2 presented with a new tumor destruction, interpreted as a local recurrence (Figure 3(a)). (e patient was therefore started on denosumab treatment. location, i.e., a metastasis elsewhere in the spine. Imaging features suspicious of malignant transformation were noted After 10 months on denosumab, the CT showed progression in cases 1 and 3. (ese cases are described in more detail into a large medial soft tissue mass which was covered by below (and in Table 2). In two other cases, mGCTB was irregular neocortex. (e bone density of the endomedullary presented with findings similar to a local recurrence (cases 4 component of the local recurrence was increased most likely and 6). A mixed response to denosumab was noted in case 5 due to denosumab. However, within the increased soft tissue that showed bone deposition and neocortex formation mass there was new osteoid matrix formation proximally, suspicious of malignant transformation in GCTB following denosumab on CT, however no decrease in tumor size. Imaging characteristics pointing towards malignant (Figure 3(b)). En bloc resection was performed, the mac- roscopic resection specimen (Figure 3(c)) and preoperative transformation are grouped by modality in Table 3. For the musculoskeletal radiologist, key findings pointing towards sagittal CT reformatted image (Figure 3(d)) showed corre- sponding endomedullary fibro-osseous matrix formation malignant transformation are: absence of fibro-osseous matrix formation and neocortex formation on CT, and (asterisk) with osteoid deposition in a posteromedial new 4 Sarcoma Table 1: Overview of mGCTB cases: histology and therapy before malignant transformation. Time first Previous surgery Interval start Primary or Sex Age at History of Histology at the Previous Case Tumor Histology at diagnosis to before malignant Denosumab Duration of denosumab to secondary (M/ diagnosis malignancy time of radiotherapy Clinical outcome nr site biopsy malignant transformation Y/N denosumab malignant malignant F) (years) Y/N transformation Y/N transformation Y/N transformation transformation Died 7 months High-grade Secondary, after malignant Y, breast Left GCTB, 1 F 54 osteosarcoma, 12 months N N Y 7 months 11 months denosumab diagnosis (cause cancer ilium H3G34W+ H3G34W+ associated unknown), lost to follow-up Died 12 months 92 months (from after malignant first diagnosis to Secondary, diagnosis due to Metastatic lesion in development of GCTB, denosumab and multiple vertebral 2 F 35 N L2 (2: Sarcoma metastasis with Y Y Y 5 months 5 months H3G34W+ surgery metastases with NOS, H3G34W+ malignant associated cervicothoracic transformation in myelum (2) compression Died 44 months Secondary, High-grade after malignant Left GCTB, Y (curettage with denosumab and 3 F 55 N osteosarcoma, 23 months N Y 10 months 10 months diagnosis due to femur H3G34W+ cement) surgery H3G34W− pulmonary associated metastases Recurrence with malignancy in Y (curettage, Left GCTB, GCTB (also areas liquid nitrogen Secondary, 4 F 37 N tarsal 12 months N N NA NA NED H3G34W + with conventional and cancellous postsurgery navicular GCTB). H3G34W bone graft) missing Highly suspicious 2 months, Secondary, GCTB, for progression to 5 M 45 N Sacrum 2 months N N Y neoadjuvant 2 months denosumab NED H3G34W + malignant GCTB, to surgery associated H3G34W+ Resection: low- grade sarcoma, radiation associated. H3G34W+ Amputation (2 yrs later): high-grade sarcoma, H3G34W+ En bloc resection GCTB, Y (multiple Secondary, of soft tissue H3G34W curettages; liquid radiotherapy Residual metastasis Right recurrence in the 6 F 27 N missing 21 years nitrogen, Y N NA NA associated present in L4, femur stump (4 yrs later): (before cancellous bone (interval 13 otherwise NED high-grade 2000) graft and cement) years) sarcoma (possibly radiation associated), however H3G34W− Intralesional resection of solitary L4 sarcoma metastasis (4.5 yrs later): H3G34W+ Sarcoma 5 Table 2: Radiological characteristics of GCTB before and after malignant transformation. Case X ray/(PET) CT at time of Tumor site MRI at time of diagnosis X ray/CT at time of transformation MRI at time of transformation nr diagnosis (ick walled lesion with central CT after 5 and 8 months of denosumab: X-ray: lytic lesion with cortex 1 Left ilium necrosis, rim enhancement, and absent fibro-osseous matrix and neocortex Not performed destruction adjacent bone marrow edema formation. Unchanged tumor size T2 hyperintense mass in (2 with large soft CT: recurrence with right paravertebral soft X-ray: lytic lesion with cortex High T2 signal intensity with some foci tissue component, epidural extension and 2 L2 tissue mass at (2. No osteolysis of the destruction and soft tissue mass of low signal myelum compression, homogeneous vertebral body enhancement postcontrast X-ray: lytic lesion with CT of the local recurrence after denosumab Lesion with high SI on T1 (partly due to pathological fracture in the showed new cortex destruction with a soft hemorrhage after fracture) and T2, 3 Left femur meta-epiphysis. CT showed tissue mass, endomedullary irregular Not performed heterogeneous. Rim enhancement after cortical scalloping and focal sclerosis and new osteoid matrix formation contrast cortex destruction proximally MRI 3.5 months postcurettage: recurrence around cancellous bone graft, higher signal intensity lesion on T2. Extension into the Lytic lesion with cortex destruction. talocalcaneal joint space. X-ray: lytic lesion in the tarsal Left tarsal Iso-intense on T1, heterogeneous low X-ray: resorption of the cancellous bone MRI 7.5 months postcurettage: increase of 4 navicular bone without cortex navicular signal intensity on T2. Extension into graft the recurrence. Extending into tarsalia and destruction lateral cuneiform and cuboid bone calcaneum. High T2 signal (marked increase of signal intensity compared to initial MRI at presentation). Multilobulated appearance. Bone marrow edema+ Lytic lesion with destruction of cortex, CT: foci of ossification in the presacral large presacral soft tissue mass. Central component (on denosumab). Neocortex max 5 Sacrum (PET)-CT: osteolysis. SUV 21 Not performed cystic/necrotic component high on T2, formation+ not enhancing. Low foci on T2 No decrease in tumor size MRI at the time of first malignant transformation: multifocal recurrence X-ray showed a well demarcated around cement/cancellous bone graft in Right lytic lesion in the lateral femoral CT: osteolysis adjacent to the cement in the 6 Not performed femur and tibia femur condyle with a pathological femur and cortex destruction MRI 2 yrs later: large heterogeneous soft fracture tissue mass in the popliteal fossa with fast enhancement after contrast 6 Sarcoma Table 3: Overview of radiological characteristics suggestive of GCTB malignant transformation, compared to baseline GCTB diagnosis. Imaging modality X-ray (PET) CT MRI ∗ ∗ Absent fibro-osseous matrix formation No increased density on CT (HU) [23] Absent neocortex formation max ∗ ∗ Absent neocortex formation No decrease in SUV [5] ∗ ∗ Stable size or increase in size of the soft tissue component Stable size or increase in size of the soft tissue component New cortex destruction New cortex destruction New cortex destruction New soft tissue mass New soft tissue mass Metastasis (new tumor localisation) Metastasis (new tumor localisation) Specific to denosumab treatment. Sarcoma 7 (a) (b) (c) (d) (e) (f) (g) (h) (i) Figure 1: Case 1, a 54-year-old female with a GCTB in the left ilium. (a) X-ray at presentation shows an osteolytic tumor with cortical destruction (arrowheads) cranially in the left iliac wing, adjacent to the sacroiliac joint. (b) MRI at the time of diagnosis; axial T2 TSE shows an expansive tumor in the left posterior aspect of the ilium with central necrosis and a peripheral thick low signal intensity rim. (c) MRI at the time of diagnosis; T1 SPIR postgadolinium (Gd) shows heterogeneous enhancement, mainly of the tumor rim and adjacent bone marrow edema in the sacrum (arrow) and ilium. (d) Axial unenhanced CT images; 5 months after starting denosumab treatment and (e) 8 months after starting denosumab treatment. Both scans showed no decrease in size and no matrix formation centrally. No thick rim of neocortex was formed. (f) Histology; morphology of first biopsy confirmed the diagnosis of conventional GCTB: mononuclear stromal cells intermixed with osteoclast-like giant cells. (e mononuclear cells have slightly enlarged nuclei and predominate over the giant cells, but since overt nuclear atypia and hyperchromasia and atypical mitoses are absent the diagnosis is still compatible with conventional giant cell tumor of bone. In the background reactive lymphocytes and some sclerosis. (g) Immunohistochemistry of the biopsy at the time of presentation: mononuclear stromal cells positive for H3G34W (scale bar 50μm). (h) Histology of resection after denosumab treatment showed malignant GCTB: atypical cells with enlarged hyperchromatic nuclei, scattered monstrous tumor cells, and atypical mitotic figures with matrix deposition suggestive of tumor osteoid. (i) Immunohistochemistry at the time of resection after denosumab treatment showed atypical stromal cells positive for H3G34W. 8 Sarcoma (a) (b) (c) (d) (e) (f) Figure 2: Case 3, a 55-year-old female with a pathological fracture of the femur with underlying GCTB. (a) X-ray at the time of diagnosis showed a pathological fracture through a well-defined osteolytic lesion with a sclerotic margin in the distal femur meta- and epiphysis, initially treated by external fixation. (b) Coronal and (c) sagittal CT images at the time of diagnosis showed the pathological fracture extending through the anterior and posterior cortices (arrows) and no internal matrix. (d) Morphology at the time of curettage shows many mononuclear stromal cells intermixed with large osteoclast-like giant cells without atypical morphological features. (e) At the time of curettage; areas with reactive woven bone with typical osteoblast lining are seen, which may be due to the clinical fracture. (f) At the time of curettage; heterogeneous positive H3G34W staining in stromal cells. increased size of the soft tissue component on CT or MRI mass lesion. Histology at the time of en bloc resection revealed a sarcomatous appearing cellular spindle cell while on denosumab treatment. proliferation with areas of tumor necrosis and the formation Regardless of the association with denosumab, findings of tumor osteoid. Histological features were in keeping with that should alert the radiologist to think of malignant a high-grade osteosarcoma (Figures 3(e) and 3(f)). (e transformation in GCTB are areas of new cortex destruction, endomedullary osteoid deposition was more regular in a new soft tissue mass, and new tumor localisations i.e., appearance and the criteria for sarcomatous progression (nonpulmonary) metastases. were not met. (erefore this fitted with denosumab induced X-ray findings suspicious for secondary mGCTB were changes. described previously, including less distinct margins and a soft tissue mass (present in 75% of cases), and cortical breakthrough (in 83% of cases) [14] and confirmed by 4. Discussion Domovitov and Healey in 2010 [15]. Grading a tumor as Six cases of secondary mGCTB are reported containing Campanacci grade III on X-ray does not differentiate be- imaging features suspicious of sarcomatous transformation tween aggressive conventional versus mGCTB [17, 24]. In in three cases. One case showed a mixed response on both studies no CT or MRI features were described, and denosumab treatment, and the remaining two showed denosumab treatment was not taken into account [14, 15]. findings in keeping with a local recurrence. Key imaging Secondary mGCTB may present with two distinct tumor findings suspicious of malignant transformation related to components on CT: a previous case-report showed a low- denosumab therapy are the absence of fibro-osseous matrix density component which histologically corresponded to a formation and neocortex formation on CT, and stable or high-grade sarcoma and a high-density component which Sarcoma 9 (a) (b) (c) (d) (e) (f) Figure 3: Case 3, same case as in Figure 2; local recurrence occurred 1 year after curettage, followed by denosumab treatment. After en bloc resection, the diagnosis of malignant GCTB was made. (a) Coronal CT image performed for follow-up approximately 1 year after surgery showed osteolysis along the medial bone-cement interface (arrows) in keeping with local recurrence. Denosumab treatment was started after this scan. (b) Coronal CT image after 10 months of denosumab therapy showed increased density in the osteolytic area of recurrence due to formation of fibro-osseous tissue (vertical arrow at the medial femoral condyle), the tumor expanded further into the soft tissues with an irregular margin (horizontal arrows). In addition, proximal to the area of local recurrence there was a newly formed component of osteoid matrix (dotted arrows), suspicious for progression to osteosarcoma. (c) Photograph of tumor macroscopy (sagittal section) after en bloc resection shows the cementum from the previous surgery, surrounded by tumor tissue extending into the soft tissue. (d) Sagittal CT reformatted after the macroscopy section (Figure 3(c)) shows endomedullary cement and holes due to previous screw tracts, surrounded by denosumab changes (asterisk). Posterior soft tissue mass is noted with osteoid matrix formation suspicious for an osteosarcoma (dotted arrows). (e) Histology at the time of resection; low power view displaying highly cellular spindle cell proliferation with areas of tumor necrosis (left) and the formation of tumor osteoid (right). Scale bar of 50 μm. (f) Tumor osteoid in high-power field fitting with the histological features of an osteosarcoma. Scale bar 50μm. 10 Sarcoma misclassification in our cases. Furthermore, in case 3, no corresponded to areas of conventional GCTB with changes related to denosumab treatment. (e lag time was 13 months biopsy was performed at the time of local recurrence. Denosumab treatment was started and mGCTB was proven [21]. Our case 3 differed in that the component with sar- comatous transformation was not osteolytic but showed after 10 months of medical treatment at the time of re- osteoid matrix formation, adjacent to the expected deno- section. (erefore, we cannot prove an association with sumab changes in the conventional GCTB component. denosumab in this case of secondary mGCTB. Tsukamoto et al. presented a case of secondary mGCTB A limitation of this case series is that imaging was done with a lag time of six months after the start of denosumab in multiple centers and not performed with standardized therapy. A CT scan performed at that time revealed en- MRI bone tumor scanning protocols including diffusion weighted imaging and dynamic contrast enhanced se- largement of a poorly defined osteoblastic mass, and a bi- opsy-confirmed high-grade sarcoma [18]. quences. Unfortunately, none of the cases in our series had MR perfusion imaging done on multiple time points. We did In summary, growth instead of a decrease in the size of the tumor during denosumab treatment is a sign pointing not have multiple timepoints of PET-CTs available to assess max SUV towards malignant transformation and this can present over time on denosumab treatment. It is known that max either as an osteolytic or osteoblastic lesion. absent decrease in SUV on PET-CT is suspicious for (e mean lag time between the start of denosumab malignant transformation of GCTB [5, 23]. treatment and malignant transformation was 7 months (range 2–11 months). (is is in accordance with previously 5. Conclusions published cases, with a lag time ranging from 6 to 13 months In only 50% of cases, radiological findings were indicative of [17, 18, 22]. In our case series, there was no clinically relevant malignant transformation, even when assessed retrospec- difference in mean lag time between patients treated with tively together with histopathology. In five out of six patients denosumab only versus patients treated with both surgery presented in this case series, malignant transformation and denosumab. (secondary mGCTB) occurred within the first year after the (e one case with surgery as the only risk factor for start of denosumab treatment or surgery. (ese findings malignant transformation had undergone curettage with stress the importance of close clinical and imaging follow-up bone grafting and the latency time to mGCTB was 9 months. in the first months after denosumab therapy for GCTB, as A hypothesis to explain surgery as the only risk factor for mGCTB tends to have rapid aggressive behavior, similar to mGCTB may be the application of (cancellous) bone other high-grade sarcomas. (e definitive diagnosis is based grafting, as the borders of the dead bone could form the on histology as radiology is not sufficient. nidus of a malignant tumor. (is mechanism has been (e medical oncologist and the radiologist play an proposed for sarcomas related to bone infarction [14, 25]. important role in the surveillance of these complex cases. On (e case with radiation-associated mGCTB had a lag denosumab treatment, the absence of the expected pain time of 13 years, in agreement with the literature, where relief in the first months after starting treatment or even new radiotherapy-associated mGCTB was shown to have a or increased pain are concerning and warrant further or new longer lag time than denosumab-associated sarcomatous diagnostic evaluation of the tumor [13, 28]. In addition to transformation, on average, eight years [14, 16, 26, 27]. that, if the known imaging response to denosumab treat- In our case series five out of six cases were women, the ment does not occur after 8–12 weeks, we recommend short greater percentage of women affected with secondary interval follow-up (for example, repeat CTafter 4 weeks) and mGCTB is in accordance with previous publications [15, 26], in case of no response, biopsy needs to be repeated. but a male predominance in secondary mGCTB has been found by others [14, 24]. Data Availability In four out of six cases, the H3G34W mutation was present at the time of diagnosis of secondary mGCTB. In one (e radiological and histopathological data used to sup- case the mutation was lost (case 3), and there was one case port the findings of this study are included within the with missing data at the time of malignant transformation article. (case 4). As the H3G34W mutation may be retained or lost in secondary mGCTB [20], it is key to re-evaluate the tissue Conflicts of Interest from the time of diagnosis of conventional GCTB to prevent misclassification. All authors declare no conflicts of interest. (e misdiagnosis of primary mGCTB as conventional GCTB is an important phenomenon, which has been Authors’ Contributions addressed in several recent publications [24, 28]. (erefore, in our case series on secondary mGCTB, two experienced KvL performed the concept and design of the study, drafted bone tumor pathologists reviewed all available biopsies, the manuscript, collected, and reviewed all radiological data. curettages, and resection specimens to verify the primary AHGC performed the histopathology and molecular pa- presentation of conventional GCTB and confirm the diag- thology data review, revision, and approval of the manu- nosis in all six cases. Nevertheless, we cannot completely rule script. ANC reviewed radiological data, revision, and out sampling error in cases only biopsy material was present approval of the manuscript. LvdH and MAJvdS obtained at the time of first diagnosis, which may have been a cause of orthopaedic clinical data, revision, and approval of the Sarcoma 11 in denosumab treatment of giant cell tumour of bone,” BMJ manuscript. 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Published: Jun 17, 2022

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