Content of this journal is licensed under a Abstract
Objective:
Chondroblastoma (CB) is a benign but locally aggressive bone tumor that may present histopathologic diagnostic challenges, particularly in atypical locations and limited biopsy specimens. Recent studies have identified recurrent mutations in the H3F3B and, less frequently, H3F3A genes, suggesting their potential diagnostic value. This study aimed to evaluate the prevalence and diagnostic utility of H3F3A and H3F3B mutations in a multicenter cohort of CB patients.
Methods:
Forty-three patients with histopathologically confirmed CB were included in a retrospective analysis. All cases were re-evaluated by 2 pathologists, and mutation analysis of H3F3A and H3F3B genes was performed using polymerase chain reaction–based Sanger sequencing.
Results:
H3F3B mutations were detected in 41 cases (95.3%), all corresponding to the Lys36Met substitution. One case (2.3%) harbored an H3F3A Gly34Trp mutation, whereas 1 case (2.3%) showed no detectable mutation. No significant histopathological differences were observed between mutation-positive and mutation-negative cases. A notable case involved a 72-year-old patient with frontal bone involvement, highlighting the diagnostic difficulty in unusual locations and older age groups.
Conclusion:
The findings demonstrate that H3F3B mutation analysis is an extremely sensitive and reliable molecular tool for confirming the diagnosis of CB. It is particularly valuable in challenging cases and especially in small biopsy samples where pathognomonic findings, such as chicken-wire calcification and chondroid matrix are not visible. Incorporation of molecular testing into targeted diagnostic workflows may improve diagnostic accuracy and assist in distinguishing CB from its histological mimics.
Level of Evidence:
Level IV, Diagnostic study.
Keywords: Bone tumor, Chondroblastoma, H3F3A, H3F3B, Mutation
Highlights
Chondroblastoma (CB) is a rare benign bone tumor that can present significant diagnostic challenges, particularly in atypical locations or limited biopsy specimens.
Giant cell lesions of bone and cartilage create difficulties in the differential diagnosis.
H3F3B gene mutations (p. Lys36Met) are highly prevalent in CB and serve as an extremely sensitive molecular diagnostic marker.
H3F3B mutation testing is most clinically valuable in diagnostically challenging scenarios, such as skull base involvement, older age groups, or when distinguishing CB from malignant mimics like CB-like osteosarcoma.
Introduction
Chondroblastoma (CB) is a benign but locally aggressive bone tumor that accounts for 1%-2% of all primary bone tumors. It has a strong predilection for the epiphyseal or apophyseal regions of long bones, typically occurring in children and young adults before epiphyseal closure.1,2 Histologically, it is composed of chondroblastic cells, islands of eosinophilic chondroid matrix, and characteristic chicken wire calcification interspersed with multinucleated osteoclast-like giant cells.3 Radiologically, CB characteristically presents as an osteolytic, epi-metaphyseal lesion with a narrow zone of transition, lobulated contours, and a thin sclerotic rim. Computed tomography imaging, particularly in the bone window, typically demonstrates this sclerotic margin along with internal chondroid-type calcifications.4
Despite these characteristic features, histopathological diagnosis of CB may be challenging, particularly in atypical locations and small biopsy specimens. Recent studies have identified somatic driver mutations in the H3F3A and H3F3B histone genes, which are present in 92% of giant cell tumors of bone (GCTB) and 95% of CB lesions, respectively.5Specifically, H3F3B mutations have been detected in over 90% of CBs, while H3F3A mutations are rare.5,6 Although H3F3A and H3F3B encode the same H3.3 histone protein, there is an ongoing discussion in the literature regarding their striking tumor-type specificity. Despite producing an identical protein, mutations in these genes are associated with distinct neoplastic entities, suggesting that factors such as cellular context, epigenetic landscape, and lineage-specific expression patterns may play a critical role. Furthermore, it remains unclear whether these mutations act merely as diagnostic markers or represent true oncogenic drivers contributing to tumorigenesis. This unresolved distinction continues to be an area of active investigation.5 Therefore, this multicenter study aims to investigate the prevalence of H3F3B and H3F3A mutations in patients diagnosed with CB and to evaluate their diagnostic utility especially in atypical cases.
Material and methods
This retrospective, multicenter study was conducted across 8 pathology departments between 2011 and 2021. The research was performed in accordance with the ethical guidelines outlined in the Declaration of Helsinki and was approved by the Ethics Committee of the Ümraniye Training and Research Hospital (Approval number: B.10.1.TKH.4.34.H.GP.0.01/162, Date: 28.05.2021).
Slides and formalin-fixed paraffin-embedded tissue blocks from patients diagnosed with CB were collected. Two independent pathologists performed a histopathological re-evaluation of the bone specimens to confirm the diagnosis of CB. The H3F3A and H3F3B genes were analyzed using polymerase chain reaction (PCR)-based Sanger sequencing on appropriate tissue blocks. Patients for whom molecular analysis could not be successfully performed due to extensive bone decalcification were excluded from the study.
Mutation analysis
Mutations in exon 2 of the H3F3A and H3F3B genes were analyzed using PCR-based Sanger sequencing. DNA concentrations were measured spectrophotometrically using a Nanodrop 1000 spectrophotometer (ThermoScientific, USA). Bidirectional sequencing traces were analyzed using SeqScape v3.0 software (Applied Biosystems, Thermo Fisher Scientific Inc., Foster City, CA, USA) and manually reviewed against the reference sequences of H3F3A (NM_002107.7) and H3F3B (NM_005324.5).
Results
A total of 43 patients with a histopathological diagnosis of CB were included in the study. Demographic data, tumor location, and mutation status are summarized in Table 1. The mean age of the patients was 17 years (range: 2-72 years), with 27 males and 16 females. The tumors were in the femur (n = 20), followed by tibia (n = 7), humerus (n = 6), talus (n = 4), patella (n = 4), calcaneus (n = 1), and frontal bone (n = 1).
Table 1.
Demographic data of the cases
| Case | Age (years) | Sex | Location | Specimen | Recurrence | H3F3B Mutation | H3F3A Mutation |
|---|---|---|---|---|---|---|---|
| 1 | 22 | Male | Right talus | Curettage | No | Positive | Negative |
| 2 | 23 | Male | Left proximal tibia | Curettage | No | Negative | Negative |
| 3 | 17 | Female | Right proximal tibia | Curettage | Yes | Positive | Negative |
| 4 | 17 | Female | Right proximal humerus | Tru-cut | No | Positive | Negative |
| 5 | 15 | Female | Right proximal humerus | Curettage | Yes | Positive | Negative |
| 6 | 15 | Male | Right proximal femur | Curettage | Yes | Positive | Negative |
| 7 | 25 | Male | Right femur | Curettage | No | Positive | Negative |
| 8 | 32 | Male | Proximal femur | Curettage | No | Positive | Negative |
| 9 | 20 | Male | Right distal femur | Curettage | No | Positive | Negative |
| 10 | 72 | Female | Frontal bone | Curettage | No | Positive | Negative |
| 11 | 17 | Female | Distal femur | Curettage | No | Positive | Negative |
| 12 | 27 | Male | Left talus | Curettage | No | Positive | Negative |
| 13 | 25 | Male | Right proximal tibia | Curettage | No | Positive | Negative |
| 14 | 12 | Female | Right distal femur | Curettage | No | Positive | Negative |
| 15 | 25 | Male | Patella | Curettage | No | Positive | Negative |
| 16 | 17 | Male | Right proximal tibia | Tru-cut | No | Positive | Negative |
| 17 | 16 | Male | Left proximal humerus | Curettage | No | Positive | Negative |
| 18 | 24 | Female | Right distal femur | Curettage | No | Positive | Negative |
| 19 | 17 | Male | Left proximal tibia | Curettage | No | Positive | Negative |
| 20 | 11 | Female | Medial condyle of right knee | Curettage | No | Positive | Negative |
| 21 | 16 | Male | Calcaneus | Curettage | No | Negative | Positive |
| 22 | 21 | Male | Talus | Curettage | No | Positive | Negative |
| 23 | 22 | Female | Proximal femur | Curettage | No | Positive | Negative |
| 24 | 27 | Female | Talus | Curettage | No | Positive | Negative |
| 25 | 15 | Male | Proximal humerus | Curettage | No | Positive | Negative |
| 26 | 21 | Male | Proximal humerus | Curettage | No | Positive | Negative |
| 27 | 14 | Male | Femoral head | Curettage | No | Positive | Negative |
| 28 | 17 | Female | Distal femur | Curettage | No | Positive | Negative |
| 29 | 14 | Male | Distal femur | Curettage | No | Positive | Negative |
| 30 | 14 | Female | Epiphysis of the right knee | Curettage | No | Positive | Negative |
| 31 | 19 | Male | Distal femur | Curettage | No | Positive | Negative |
| 32 | 12 | Female | Femur trochanter | Curettage | No | Positive | Negative |
| 33 | 16 | Male | Medial condyle of femur | Curettage | No | Positive | Negative |
| 34 | 16 | Male | Distal femur | Curettage | No | Positive | Negative |
| 35 | 29 | Male | Proximal humerus | Curettage | No | Positive | Negative |
| 36 | 19 | Male | Proximal tibia | Curettage | No | Positive | Negative |
| 37 | 39 | Female | Femur | Curettage | No | Positive | Negative |
| 38 | 16 | Female | Distal femur | Curettage | No | Positive | Negative |
| 39 | 17 | Male | Medial condyle of femur | Curettage | No | Positive | Negative |
| 40 | 21 | Male | Patella | Curettage | No | Positive | Negative |
| 41 | 21 | Male | Proximal tibia | Curettage | No | Positive | Negative |
| 42 | 34 | Male | Distal femur | Curettage | No | Positive | Negative |
| 43 | 33 | Female | Femur | Curettage | No | Positive | Negative |
Tru-cut biopsy was performed in only 1 patient, while curettage materials were obtained from the remaining patients. Four patients had recurrent tumors, while the others had primary tumors. Histopathological examination confirmed the diagnosis of CB in all cases (Figure 1).
Figure 1.
Histopathological examination of chondroblastoma demonstrating characteristic pericellular “chicken-wire” calcification (arrows) and interspersed multinucleatedgiant cells (asterisk) (H&E, ×40).
Polymerase chain reaction–based Sanger sequencing revealed H3F3B mutations in 41 patients (95.3%) (Figure 2) and an H3F3A mutation in 1 patient (2.3%). The Lys36Met alteration was detected in the H3F3B gene in 41 cases, while the H3F3A gene showed a Gly34Trp alteration in 1 case. One patient (2.3%) had no detectable mutation in either gene. All patients, regardless of their mutation status, showed typical histomorphological features consistent with CB, and no significant histopathological differences were observed between the H3F3B mutation-positive, H3F3A mutation-positive, and mutation-negative cases.
Figure 2.
Electropherogram showing the p.Lys36Met mutation in exon 2 of the H3F3B gene detected by polymerase chain reaction–based Sanger sequencing.
The patient harboring the H3F3A mutation was a 16-year-old boy who presented with a calcaneal mass. Magnetic resonance imaging (MRI) revealed a lesion that completely occupied the calcaneus, destroying the bone structure and containing hyperdense areas compatible with calcification, with widespread cystic openings measuring up to 96 × 72 × 65 mm in size (Figure 3). Microscopically, the tumor demonstrated typical CB features with polygonal chondroblasts showing characteristic nuclear grooves, multinucleated giant cells, and areas of chondroid matrix formation (Figure 4).
Figure 3.
Mass lesion with calcified chondroid matrix content in an expansive appearance completely occupied the calcaneus (96x72x65 mm): a: Magnetic resonance imaging (MRI) T1-weighted sagittal image b: MRI T2-weighted sagittal image c: Computed tomography (CT) axial image d: CT sagittal reformatted image.
Figure 4.
Microscopic appearance of the calcaneal tumor showing polygonal chondroblasts with characteristic nuclear grooves (arrow), multinucleated giant cells, and areas of chondroid matrix formation (asterisks) (H&E, ×20).
The mutation-negative patient in the study was a 23-year-old man with a tibial tumor. Magnetic resonance imaging revealed an irregular, well-demarcated mass measuring 20 × 17 × 12 mm in the posteromedial condyle of the tibia, with focal cortical destruction. Microscopically, the tumor exhibited classic histopathological features of CB, including sheets of polygonal cells with nuclear grooves, scattered multinucleated giant cells, and characteristic chicken-wire calcification pattern, confirming the diagnosis despite the absence of detectable mutations (Figure 5).
Figure 5.
Histopathological features of the mutation-negative tibial tumor exhibiting sheets of polygonal cells with grooved nuclei, scattered multinucleated giant cells, and a characteristic chicken-wire calcification pattern (arrows) (H&E, ×4).
The most notable case in the cohort was a patient with frontal bone involvement, who was also the oldest participant. This 72-year-old woman presented with a 1-year history of progressive vision loss. Brain MRI detected a well-defined, heterogeneously enhancing lesion extending from the ethmoid bone to the inferior aspect of the frontal lobe, displaying characteristic signal intensity patterns (Figure 6). Microscopically, the tumor showed classic features of CB, with polygonal chondroblasts exhibiting characteristic nuclear grooves and moderate cytoplasmic eosinophilia. The tumor cells were arranged in sheets with interspersed multinucleated giant cells and areas of chondroid matrix formation. The characteristic chicken-wire calcification pattern was also prominently observed (Figure 7).
Figure 6.
Brain contrast-enhanced magnetic resonance imaging T1-weighted axial sequence of a 72-year-old female demonstrating a well-defined, heterogeneously enhancing lesion extending from the ethmoid bone to the inferior aspect of the frontal lobe (arrow).
Figure 7.
Microscopic examination of the frontal bone tumor revealing tumor cells arranged in sheets with interspersed multinucleated giant cells (arrows) (H&E, ×4).
Discussion
The histopathological diagnosis of CB can be straightforward in classic cases presenting with typical morphology and characteristic radiological findings. However, the differential diagnosis becomes significantly challenging when tumors occur in atypical anatomical locations, present in older age groups, or when only limited biopsy material is available. In such scenarios, distinguishing CB from other giant cell-rich or chondroid lesions is critical. Therefore, molecular studies, particularly the identification of H3F3B mutations, have gained immense importance in recent years as a reliable diagnostic adjunct.7
The H3F3A and H3F3B genes are located at 1q42.12 and 17q25.1, respectively, and encode identical H3.3 core histone proteins. Mutations in these genes play a significant role in the pathogenesis of specific bone and brain tumors.8 Behjati et al reported p. Lys36Met alterations in the H3F3B gene in 95% of CB cases and the H3F3A gene in 92% of GCTB.5 Consistent with the literature, the study demonstrated a high prevalence of H3F3B mutations, detecting the Lys36Met alteration in 95.3% (41/43) of the CB cohort, while an H3F3A mutation (Gly34Trp) was observed in only 1 case.
Other studies have corroborated these high mutation frequencies. Cleven et al investigated the frequency of H3F3A, H3F3B, IDH1, and IDH2 mutations in GCTB, CB, and other giant cell–containing tumors using Sanger sequencing.9 They found that 70% of CB cases harbored H3F3B mutations, with no mutations detected in other giant cell-containing tumors. In another study comparing CB patients with those suspected of having CB, immunohistochemical analysis revealed significant differences in H3K36M staining, with PCR results consistent with immunohistochemical findings.10 Among patients with suspected CB, no H3F3B mutations were detected, while 1 patient with a giant cell tumor had a G34W mutation. Amary et al evaluated the expression of the K36M-mutated protein in 85 CB patients, identifying H3F3 p.K36M mutations in 82 patients, with only 3 lacking H3F3A/H3F3B mutations.11 In the study, 41 of 43 patients with a histomorphologically confirmed diagnosis of CB had H3F3B mutations detected by PCR-based Sanger sequencing, yielding a sensitivity of 95%. One patient (2.3%) had an H3F3A mutation, consistent with previous studies. Behjati et al also identified H3F3A mutations in 5 of 73 CB cases.5 It is acknowledged that immunohistochemical analysis has several important advantages including lower cost, wider availability, and easier interpretation in routine practice. Although immunohistochemical analysis has high specificity and sensitivity for CB diagnosis, mutation analysis method was used, which is considered the gold standard for molecular diagnosis, in this study. Both methods have complementary roles in the diagnostic workup of CB, and the choice between them may depend on institutional resources and clinical context.
The clinical implications of H3F3B mutation analysis become particularly evident in atypical presentations, such as skull base involvement. The cohort included a 72-year-old female with a CB extending from the ethmoid bone to the frontal lobe. To the best of current knowledge, only 1 other case of CB with frontal bone involvement has been reported in the literature, which involved an 8-year-old child.12 Therefore, the patient represents the second reported case with this unusual location, and notably, the first in an elderly patient. Given their rarity—especially in older individuals—skull base CBs are frequently misdiagnosed as chordomas, meningiomas, or other skull base tumors, as they are not typically considered in the initial differential diagnosis.13 Although skull base CBs may radiologically mimic chordomas and meningiomas, certain features aid in differentiation. Chordomas typically show midline localization and markedly high T2 signal intensity, whereas meningiomas are extra-axial lesions with hyperostosis and a dural tail sign.14 In contrast, CBs tend to present as well-defined osteolytic lesions with possible chondroid calcifications and lower T2 signal intensity.4 Nevertheless, significant radiological overlap exists. In such unusual locations and age groups, H3F3B mutation testing serves as a definitive molecular tool to confirm the diagnosis and prevent unnecessary aggressive treatments.15In chondroblastomas, satisfactory functional outcomes can be achieved even in cases of recurrence through early diagnosis, aggressive curettage, and the use of local adjuvants, with grafting remaining the first-line reconstructive option.16
The histopathological differential diagnosis of CB primarily includes GCTB, aneurysmal bone cysts, chondromyxoid fibromas, clear cell chondrosarcomas, and CB-like osteosarcomas.17 These tumors may exhibit overlapping morphological features, such as the presence of osteoclast-like giant cells, chondroid or myxoid matrix, and variable cellular atypia. Molecular analyses are highly valuable for differentiating these challenging entities. For instance, detecting H3F3A mutations supports a diagnosis of GCTB,18,19 while USP6 gene rearrangements are characteristic of primary aneurysmal bone cysts,20 and GRM1 upregulation is seen in chondromyxoid fibromas.21 Furthermore, distinguishing CB from CB-like osteosarcoma is critical for treatment planning; the latter lacks the characteristic H3F3B K36M mutation and demonstrates a distinct genomic landscape with different copy number alterations.22 Clear cell chondrosarcoma, on the other hand, has no specific genetic alterations identified to date.23 The findings demonstrate that detecting H3F3B mutations using PCR-based Sanger sequencing is a valuable molecular tool for diagnosing CB and distinguishing it from these morphologically similar tumors.
Several additional limitations of this study should be acknowledged. First, the retrospective design and multicenter nature of the cohort may have introduced selection bias and inter-institutional variability, particularly in tissue handling, fixation, and decalcification protocols, all of which can directly affect DNA quality and mutation detection rates. Second, although Sanger sequencing is widely accepted, its relatively limited sensitivity compared to more advanced techniques such as next-generation sequencing or digital PCR raises the possibility of false-negative results, especially in samples with low tumor cellularity or significant necrosis. In addition, the targeted nature of the analysis, focusing primarily on hotspot regions, may have limited the detection of rare or non-canonical variants. Third, the lack of complementary immunohistochemical analysis (e.g., H3K36M) or validation using alternative molecular methods limits the ability to cross-confirm the findings. In addition, the absence of a control group comprising histological mimics restricts the assessment of the true diagnostic specificity of H3F3B mutations within this cohort. Finally, although clinical and demographic data were available, no formal analysis was performed to explore potential associations between mutation status and clinical outcomes, such as recurrence or tumor behavior, which may represent an area for future investigation. Moreover, the mutation-negative case was not subjected to further molecular or technical validation, and therefore the possibility of a false-negative result or the presence of alternative genetic alterations cannot be excluded.
In conclusion, the findings demonstrate that detecting H3F3B mutations using PCR-based Sanger sequencing is an extremely sensitive and valuable molecular tool for diagnosing CB and distinguishing it from morphologically similar tumors. While H3F3B mutations are highly prevalent in CB, routine molecular testing may not be strictly necessary for classic cases presenting with typical clinico-radiological and histopathological features. Instead, H3F3B mutation testing is most clinically justified and provides the greatest diagnostic benefit in challenging scenarios where conventional histopathological assessment is insufficient. These include cases with equivocal histomorphology, tumors occurring in unusual anatomical locations (e.g., skull base or flat bones), patients outside the typical age range, or when distinguishing CB from malignant mimics, such as CB-like osteosarcoma, is critical for appropriate clinical management.
Funding Statement
The authors declare that this study has received no financial support.
Footnotes
Artificial Intelligence Usage Statement: The authors declared that no Artificial Intelligence tool was used in the preparation of the manuscript.
Ethics Committee Approval: Ethical committee approval was received from the Ethics Committee of Ümraniye Training and Research Hospital (Approval no: B.10.1.TKH.4.34.H.GP.0.01/162, Date: May 28, 2021).
Informed Consent: Written informed consent was obtained from the patients who agreed to take part in the study.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept – İ.T., İ.Y.; Design – İ.T., İ.Y.; Supervision – İ.T., G.U.; Resources – İ.T., İ.Y.; Materials – İ.T., İ.Y.; Data Collection and/or Processing – İ.T., İ.Y., A.C., C.C., N.C., K.T., S.C., H.İ., G.U.; Analysis and/or Interpretation – İ.T., H.İ., G.U.; Literature Search – İ.T.; Writing – İ.T.; Critical Review – İ.T., G.U.
Declaration of Interests: The authors have no conflict of interest to declare.
Data Availability Statement:
The data that support the findings of this study are available on request from the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available on request from the corresponding author.