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Bone Tumours: From Molecular Pathology to Clinical Practice

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A special issue of Diagnostics (ISSN 2075-4418). This special issue belongs to the section "Pathology and Molecular Diagnostics".

Deadline for manuscript submissions: closed (28 February 2025) | Viewed by 9751

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Special Issue Editors

Prof. Dr. Carolin Mogler

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Guest Editor

Institute of Pathology, Technical University of Munich, 81675 Munich, Germany
Interests: soft tissue sarcomas; bone tumor

Prof. Dr. Gernot Jundt

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Bone Tumor Reference Centre, Institute of Pathology, University Hospital Basel, University of Basel, 4031 Basel, Switzerland
Interests: bone tumor

Special Issue Information

Since the end of the 1980s, there has been little progress in the treatment of malignant bone tumors. However, the introduction of molecular diagnostics in pathology has led to notable advances in the field of bone tumors, particularly in diagnostics but also in therapy.

Better distinction between individual tumor types (osteoblastoma versus osteosarcoma; fibrous dysplasia versus low-grade central osteosarcoma) became possible, which had a direct impact on therapy decisions and modalities or evolved new therapeutic options (denosumab therapy in giant cell tumors of bone). Malignant tumors, which were previously considered as one group, albeit being a highly heterogeneous group, e.g., undifferentiated small round cell sarcomas of bone and soft tissue, could now be subdivided molecularly and genetically as distinct entities, and initial studies indicate that the therapy for each might also differ. So-called “tumor-like lesions,” which were previously considered reactive, also exhibited genetic aberrations that suggested their classification as true neoplasms (solitary bone cyst, non-ossifying bone fibroma).

The detection of specific targets, which were often based on translocations, enabled targeted therapies (Langerhans cell histiocytosis, Erdheim–Chester disease)

The improvement in imaging methods also resulted in improved surgical options, which were further expanded by advances in radiation therapy (particle and heavy ion therapy).

This Special Issue on bone tumors provides an overview of the latest diagnostic and therapeutic achievements in the field of bone tumors.

Prof. Dr. Carolin Mogler
Prof. Dr. Gernot Jundt
Guest Editors

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Keywords

bone tumors
molecular diagnostics
soft tissue sarcomas

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Published Papers (9 papers)

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16 pages, 5355 KiB

Open AccessArticle

Clinical and Pathological Profile of Children and Adolescents with Osteosarcoma

by Andrei Ivan, Elena Cojocaru, Paul Dan Sirbu, Dina Roșca Al Namat, Ștefan Dragoș Tîrnovanu, Lăcrămioara Ionela Butnariu, Jana Bernic, Valentin Bernic and Elena Țarcă

Diagnostics 2025, 15(3), 266; https://doi.org/10.3390/diagnostics15030266 - 23 Jan 2025

Cited by 1 | Viewed by 951

Abstract

Introduction: Osteosarcoma (OS) is the most common type of primary malignant bone and cartilage tumour. Because of the remarkable developments in technology, remarkable progress has been made in the medical field regarding the diagnosis and management of OS patients. The aim of the study is to describe the clinical and pathological profile of paediatric patients with osteosarcoma and to identify potential prognostic factors for an unfavourable outcome in our country. Methods: We conducted a retrospective study of all children and adolescents with musculoskeletal tumours diagnosed and treated at our tertiary Orthopaedic Department for a period of 10 years. Results: A group of 65 children and adolescents with osteosarcoma who benefited from diagnosis, neoadjuvant, adjuvant and surgical treatment in the Emergency Clinical Hospital for Children “Sfânta Maria” Iasi, România, was analysed. The average age at the time of diagnosis was 12.9 years. The analysis revealed a higher frequency for male patients in the case of femur and tibia locations and a significantly higher frequency of osteosarcoma in the scapula and clavicle in female patients, while OS in the humerus was found only in male patients (χ² = 19.46, p = 0.0149). The most frequent histopathological subtype was osteoblastic osteosarcoma, but there was no significant correlation with the gender or the age of the patients (χ² = 0.73, p = 0.863 and χ² = 0.843, p = 0.839). The results indicated instead a significantly (p = 0.0185) lower age values of patients with undifferentiated osteosarcomas, the average age being 9.4 years ± 2.1 SD. After performing a multivariate logistic regression analysis for the risk of death based on clinical parameters, we found that high tumoural grading increases the risk of death 2.8 times, pleomorphic histological subtype increases the risk of death 3.5 times, and stage IV TNM increases this risk 5.9 times. Conclusions: For the north-eastern geographical part of Romania, the epidemiological and clinical profile of a child with osteosarcoma is a 13-year-old boy with a femoral or tibia tumour or a 12-year-old girl with a femoral, tibia, scapula or clavicle tumour, both coming from a rural area. The tumour has around 12 cm diameter and is a differentiated osteoblastic osteosarcoma. The survival rate at 10 years is 63%. Tumour grading, histological subtype and TNM staging significantly influence the probability of death and could be important prognostic parameters for patients with osteosarcoma. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

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17 pages, 3729 KiB

Open AccessArticle

First Experiences with Fusion of PET-CT and MRI Datasets for Navigation-Assisted Percutaneous Biopsies for Primary and Metastatic Bone Tumors

by Hagen Fritzsche, Alexander Pape, Klaus-Dieter Schaser, Franziska Beyer, Verena Plodeck, Ralf-Thorsten Hoffmann, Patricia Hahlbohm, Elisabeth Mehnert and Anne Weidlich

Diagnostics 2025, 15(1), 63; https://doi.org/10.3390/diagnostics15010063 - 29 Dec 2024

Cited by 1 | Viewed by 956

Abstract

Background: The aim of this study was to compare the technique of navigation-assisted biopsy based on fused PET and MRI datasets to CT-guided biopsies in terms of the duration of the procedure, radiation dose, complication rate, and accuracy of the biopsy, particularly in anatomically complex regions. Methods: Between 2019 and 2022, retrospectively collected data included all navigated biopsies and CT-guided biopsies of suspected primary bone tumors or solitary metastases. Navigation was based on preoperative CT, PET-CT/-MRI, and MRI datasets, and tumor biopsies were performed using intraoperative 3D imaging combined with a navigation system. Results: A total of 22 navigated (main group: m/f = 10/12, mean age: 56 yrs.) and 57 CT-guided biopsies (reference group: m/f = 36/21, mean age: 63 yrs.) were performed. Patients were grouped according to anatomic sites (pelvis, spine, extremities, thorax). The duration of the procedure in the reference group was significantly shorter than in the main group, particularly in the spine. The effective radiation dose was in the same range in both groups (main/reference group: 0.579 mSv and 0.687 mSv, respectively). In the reference group, a re-biopsy had to be performed in nine patients (diagnostic yield: 84%). A total of four major and three minor complications occurred in the reference group. Conclusions: Navigation-assisted percutaneous tumor biopsy resulted in correct, histologically useable diagnoses in all patients and reached a higher accuracy and first-time success rate (diagnostic yield: 100%) in comparison to CT-guided biopsies. The fusion of PET, CT, and MRI datasets enables us to combine anatomical with metabolic information. Consequently, target selection was improved, and the rate of false negative/low-grade sampling errors was decreased. Radiation exposure could be kept at a comparable level, and the durations of both procedures were comparable to conventional methods. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

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16 pages, 2766 KiB

Open AccessArticle

Pediatric Bone Tumors: Location and Age Distribution of 420 Cases

by Sebastian Breden, Maximilian Stephan, Florian Hinterwimmer, Sarah Consalvo, Ulrich Lenze, Rüdiger von Eisenhart-Rothe, Carolin Mogler, Alexandra S. Gersing and Carolin Knebel

Diagnostics 2024, 14(22), 2513; https://doi.org/10.3390/diagnostics14222513 - 9 Nov 2024

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Abstract

Background/Objectives: One of the most important diagnostic tools in bone tumors is X-rays. Preliminary and, in the case of some benign lesions, definitive diagnoses are formed using this basic tool. Part of the decision making in this stage is based on statistical probability using the patient’s age, as well as the incidence and predilection sites of different entities. The information used today is based on older and fragmented data. To verify the underlying principles, we retrospectively evaluated all bone tumors in children and adolescents treated by our tertiary center in the last 20 years. Methods: For this retrospective study, patients under the age of 18 years suffering from histopathologically verified bone tumors were evaluated. Data were retrieved from our local musculoskeletal tumor database. Results: We were able to include 420 children treated for bone tumors in our tertiary center. The cohort consisted of 335 benign and 85 malignant lesions. The most common lesions were 137 osteochondromas; the malignant tumors consisted mainly of osteosarcomas (53) and Ewing’s sarcomas (28). The primary predilection sites were the metaphyses of long bones. Conclusions: We were able to confirm and supplement the fragmentary data of these rare diseases using our own cohort. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

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11 pages, 984 KiB

Open AccessArticle

Chondrosarcoma of the Pelvis and Extremities: A Review of 77 Cases of a Tertiary Sarcoma Center with a Minimum Follow-Up of 10 Years

by Sebastian Breden, Maximilian Stephan, Carolin Knebel, Florian Lenze, Florian Pohlig, Florian Hinterwimmer, Sarah Consalvo, Carolin Mogler, Rüdiger von Eisenhart-Rothe and Ulrich Lenze

Diagnostics 2024, 14(19), 2166; https://doi.org/10.3390/diagnostics14192166 - 28 Sep 2024

Cited by 1 | Viewed by 1110

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Background: Chondrosarcomas (CS) are a rare and heterogenic group of primary malignant bone tumors. In the literature, data on prognostic factors in chondrosarcomas are scarce, and most studies are limited by a short follow-up. The aim of this retrospective study was therefore to determine factors associated with the survival and local recurrence of chondrosarcomas and to compare the results with previous studies. Methods: We retrospectively evaluated 77 patients who were treated for chondrosarcoma of the extremities or pelvis at our tertiary sarcoma center between 1998 and 2007. Patient-related data (age, sex, etc.), tumor characteristics (localization, grading, presence of metastases, etc.), and treatment-related data (previous surgical treatment, type of local treatment, surgical margins, etc.) were evaluated and analyzed for possible correlation with patients’ outcomes. A statistical analysis was performed, including multivariate analysis. Results: The mean survival in our patients was 207 months, which resulted in a five-year survival rate of 76%. Negative prognostic factors for survival were histopathological grading, a patient aged over 70 years, and metastatic disease. The quality of the resection (clear or contaminated margins) negatively influenced both the development of local recurrence and survival too, at least in the univariate analysis. In contrast, factors such as tumor localization (extremities vs. pelvis), pathological fractures, or an initial inadequate resection elsewhere had no significant effect on survival. Conclusions: In accordance with results in the literature, the survival of patients with chondrosarcomas is mainly influenced by factors such as tumor grading, age, and metastases. However, complete resection remains paramount for the outcome in patients with chondrosarcoma—a primary malignant bone tumor with limited alternative treatment options. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

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10 pages, 1217 KiB

Open AccessArticle

C-Reactive Protein Pretreatment-Level Evaluation with Histopathological Correlation for Chondrosarcoma Prognosis Assessment—A 15-Year Retrospective Single-Center Study

by Sarah Consalvo, Florian Hinterwimmer, Maximilian Stephan, Sebastian Breden, Ulrich Lenze, Jan Peeken, Rüdiger von Eisenhart-Rothe and Carolin Knebel

Diagnostics 2024, 14(13), 1428; https://doi.org/10.3390/diagnostics14131428 - 4 Jul 2024

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Abstract

Background: An aberrant cellular microenvironment characterized by pathological cells or inflammation represents an added risk factor across various cancer types. While the significance of chronic inflammation in the development of most diffuse tumors has been extensively studied, an exception to this analysis exists in the context of chondrosarcomas. Chondrosarcomas account for 20–30% of all bone sarcomas, with an estimated global incidence of 1 in 100,000. The average age at diagnosis is 50, and over 70% of patients are over 40. This retrospective study aimed to examine the role of C-reactive protein (CRP) as a prognostic factor in relation to the histopathological findings in chondrosarcoma. Methods: In this retrospective study, 70 patients diagnosed with chondrosarcoma and treated between 2004 and 2019 were included. Preoperative CRP levels were measured in mg/dL, with non-pathological values defined as below 0.5 mg/dL. Disease-free survival time was calculated from the initial diagnosis to events such as local recurrence or metastasis. Follow-up status was categorized as death from disease, no evidence of disease, or alive with disease. Patients were excluded if they had insufficient laboratory values, missing follow-up information, or incomplete histopathological reports. Results: The calculated risk estimation of a reduced follow-up time was 2.25 timed higher in the patients with a CRP level >0.5 mg/dL (HR 2.25 and 95% CI 1.13–4.45) and 3 times higher in patients with a tumor size > pT2 (HR 3 and 95% CI 1.59–5.92). We can easily confirm that risk factors for reduced prognosis lie in chondrosarcoma high grading, preoperative pathological CRP- level, and a size > 8 cm. Conclusions: A pretreatment CRP value greater than 0.5 mg/dL can be considered a sensitive prognostic and risk factor for distant metastasis for chondrosarcoma patients. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

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16 pages, 1691 KiB

Open AccessArticle

Impact of CDK Inhibitors on TBXT Expression in Chordoma Cell Lines Including the First Stable Cell Line of a High-Grade Chordoma

by Sarah Bette, Luisa Haase, Juliane Nell, Thomas Grieser, Alexandra von Baer, Markus Schultheiss, Ralf Marienfeld, Peter Möller, Thomas F. E. Barth and Kevin Mellert

Diagnostics 2024, 14(10), 1028; https://doi.org/10.3390/diagnostics14101028 - 16 May 2024

Cited by 1 | Viewed by 1715

Abstract

Chordomas are very rare malignant neoplasms of the bone occurring almost exclusively along the spine. As the tumours are thought to arise from notochordal remnants, the vast majority of chordomas express the TBXT gene, resulting in detectable nuclear amounts of its gene product brachyury. This T-Box transcription factor is commonly recognised as being essential in chordoma cells, and limiting TBXT expression is thought to be the key factor in controlling this tumour. Although the tumour is rare, distinct molecular differences and vulnerabilities have been described with regard to its location and the progression status of the disease, rendering it mandatory for novel cell lines to reflect all relevant chordoma subtypes. Here, we describe a novel chordoma cell line arising from the pleural effusion of a disseminated, poorly differentiated chordoma. This cell line, U-CH22, represents a highly aggressive terminal chordoma and, therefore, fills a relevant gap within the panel of available cell culture models for this orphan disease. CDK7 and CDK9 inhibition was lately identified as being effective in reducing viability in four chordoma cell lines, most likely due to a reduction in brachyury levels. In this study, we determined the capability of the CDK7 inhibitor THZ1 and the CDK1/2/5/9 inhibitor dinaciclib to reduce TBXT expression at mRNA and protein levels in a broad range of nine cell lines that are models of primary, recurrent, and metastasised chordoma of the clivus and the sacrum. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

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25 pages, 6990 KiB

Open AccessReview

Non-Coding RNAs in Diagnostic Pathology of High-Grade Central Osteosarcoma

by Albert Roessner, Sabine Franke, Julian Schreier, Sarah R. Ullmann and Franziska S. Karras

Diagnostics 2025, 15(11), 1355; https://doi.org/10.3390/diagnostics15111355 - 28 May 2025

Abstract

A histological evaluation remains the cornerstone of diagnosing highly malignant osteosarcoma, having demonstrated its efficacy and reliability over several decades. However, despite these advancements, misdiagnoses with severe consequences, including inadequate surgical procedures, continue to occur. Consequently, there is a pressing need to further enhance diagnostic security. Adjunct immunohistochemical approaches have demonstrated significant effectiveness in regard to cancer diagnostics, generally. However, their utility for identifying highly malignant osteosarcoma is limited. Molecular genetic findings have significantly improved the diagnosis of Ewing’s sarcoma by identifying specific translocations and have been used to detect specific IDH gene mutations in chondrosarcoma. Nevertheless, molecular genetic alterations in highly malignant osteosarcoma exhibit a high degree of complexity, thereby limiting their diagnostic utility. Given that only 1–2% of the human genome comprises protein-coding sequences, the growing number of non-coding regulatory RNAs, which are increasingly being elucidated, has garnered substantial attention in the field of clinical cancer diagnostics. Over the past several years, patterns of altered non-coding RNA expression have been identified that facilitate the distinction between benign and malignant tumors in various organs. In the field of bone tumors, the experience of this approach has been limited thus far. The divergent expression of microRNAs has demonstrated utility for differentiating osteosarcoma from osteoblastoma and discriminating between osteosarcoma and giant-cell tumors of bone and fibrous dysplasia. However, the application of non-coding RNA expression patterns for the differential diagnosis of osteosarcoma is still in its preliminary stages. This review provides an overview of the current status of non-coding RNAs in osteosarcoma diagnostics, in conjunction with a histological evaluation. The potential of this approach is discussed comprehensively. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

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22 pages, 369 KiB

Open AccessReview

The Role of Epithelial–Mesenchymal Transition in Osteosarcoma Progression: From Biology to Therapy

by Andrei-Valentin Patrașcu, Elena Țarcă, Ludmila Lozneanu, Carmen Ungureanu, Eugenia Moroșan, Diana-Elena Parteni, Alina Jehac, Jana Bernic and Elena Cojocaru

Diagnostics 2025, 15(5), 644; https://doi.org/10.3390/diagnostics15050644 - 6 Mar 2025

Viewed by 803

Abstract

Osteosarcoma (OS) is the most common primary malignant bone tumor, predominantly affecting children, adolescents, and young adults. Epithelial–mesenchymal transition (EMT), a process in which epithelial cells lose their cell–cell adhesion and gain migratory and invasive properties, has been extensively studied in various carcinomas. However, its role in mesenchymal tumors like osteosarcoma remains less explored. EMT is increasingly recognized as a key factor in the progression of osteosarcoma, contributing to tumor invasion, metastasis, and resistance to chemotherapy. This narrative review aims to provide a comprehensive overview of the molecular mechanisms driving EMT in osteosarcoma, highlighting the involvement of signaling pathways such as TGF-β, transcription factors like Snail, Twist, and Zeb, and the role of microRNAs in modulating EMT. Furthermore, we discuss how EMT correlates with poor prognosis and therapy resistance in osteosarcoma patients, emphasizing the potential of targeting EMT for therapeutic intervention. Recent advancements in understanding EMT in osteosarcoma have opened new avenues for treatment, including EMT inhibitors and combination therapies aimed at overcoming drug resistance. By integrating biological insights with clinical implications, this review underscores the importance of EMT as a critical process in osteosarcoma progression and its potential as a therapeutic target. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

10 pages, 199 KiB

Open AccessReview

Unplanned Excision in Soft Tissue Sarcoma: Current Knowledge and Remaining Gaps

by Tomoki Nakamura and Masahiro Hasegawa

Diagnostics 2025, 15(4), 453; https://doi.org/10.3390/diagnostics15040453 - 13 Feb 2025

Viewed by 601

Abstract

Soft tissue sarcoma (STS) is a rare and heterogeneous disease, which can result in surgeons not considering STS as a differential diagnosis when they encounter a lump. However, unplanned excision (UE) often occurs in nonspecialized sarcoma centers. Before re-excision (RE) after UE, radiological examinations such as magnetic resonance imaging (MRI) should be performed to determine the surgical margin and conduct a pathological evaluation of the UE. However, differentiating between residual tumor and postsurgical changes remains challenging because of the presence of postoperative edema, hematoma, and seroma on MRI. Propensity score matching analysis showed that patients with STS who underwent RE after UE did not have higher mortality or local recurrence rates than those who underwent planned excision (PE), while RE often requires reconstruction procedures. From the patient’s perspective, one operation (PE) is better than two (UE and RE) because it reduces hospital stays and time away from work. Continuous education about STS is necessary for all surgeons to reduce the incidence of UE. Full article

(This article belongs to the Special Issue Bone Tumours: From Molecular Pathology to Clinical Practice)

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