The 2020 WHO Classification of Tumors of Bone: An Updated Review.

Bone tumors are a rare and heterogeneous group of neoplasms that occur in the bone. The diversity and considerable morphologic overlap of bone tumors with other mesenchymal and nonmesenchymal bone lesions can complicate diagnosis. Accurate histologic diagnosis is crucial for appropriate management and prognostication. Since the publication of the fourth edition of the World Health Organization (WHO) classification of tumors of soft tissue and bone in 2013, significant advances have been made in our understanding of bone tumor molecular biology, classification, prognostication, and treatment. Detection of tumor-specific molecular alterations can facilitate the accurate diagnosis of histologically challenging cases. The fifth edition of the 2020 WHO classification of tumors of soft tissue and bone tumors provides an updated classification scheme and essential diagnostic criteria for bone tumors. Herein, we summarize these updates, focusing on major changes in each category of bone tumor, the newly described tumor entities and subtypes of existing tumor types, and newly described molecular and genetic data.

Skull Base Chordomas and Chondrosarcomas.

Skull base chordomas account for less than 0.2% and chondrosarcomas for less than 0.15% of all intracranial tumors. Although their clinical and imaging presentations are similar, they derive from different origins. Chordomas arise from embryonic remnants of the primitive notochord and chondrosarcomas from primitive mesenchymal cells or from the embryonic rest of the cranial cartilaginous matrix. Both entities are characterized by infiltration and destruction of the surrounding bone and soft tissue and a high locoregional recurrence rate. Chondrosarcomas, when treated with similar complex strategies, display a much better prognosis than chordomas. The overall survival is approximately 65% for chordomas and 80% for chondrosarcomas at 5 years and 30 and 50%, respectively, at 10 years. Chordomas are divided into the following 3 histological types: classical (conventional), chondroid, and dedifferentiated. Chondrosarcomas have conventional, mesenchymal, clear cell, and dedifferentiated subgroups. Both tumor entities often present with nonspecific symptoms, and headaches are the most reported initial symptom. Computed tomography and magnetic resonance imaging are required to determine the tumor localization and the extent of tumor growth. The treatment philosophy is to maximize tumor resection, minimize morbidity, and preserve function. Neurosurgical approaches commonly used for the resection of intracranial chordomas and chondrosarcomas are transsphenoidal, transbasal, cranio-orbitozygomatic, transzygomatic extended middle fossa, transcondylar, and transmaxillary approaches. Chordomas and chondrosarcomas are not sensitive to chemotherapy and there are no approved drugs for their treatment. The present treatment concept is a combination of surgical resection with a maximal excision and preserving patients' quality of life by adjuvant radiotherapy for both chordomas and chondrosarcomas.

Prognostic Factors and Treatment Options for Patients with High-Grade Chondrosarcoma.

BACKGROUND The goal of this study was to determine the prognostic factors exclusive for high-grade chondrosarcoma and whether adjuvant radiotherapy could achieve better overall survival (OS) or cancer-specific survival (CSS) for patients with high-grade chondrosarcoma. MATERIAL AND METHODS Surveillance, Epidemiology, and End Results (SEER) cancer registry database was utilized to extract the chondrosarcoma cases diagnosed between 1973 and 2014. Among these cases, the histological grades of poorly differentiated (grade 3) and undifferentiated (grade 4) were categorized as high-grade and included in this study. Chondrosarcoma OS and CSS were the primary outcomes in the present study. The log-rank test was performed for univariate analysis, and the Cox regression model was conducted for multivariate analysis. RESULTS A total of 743 patients with high-grade chondrosarcoma were identified in this study (430 cases were poorly differentiated tumors, and 313 cases were undifferentiated tumors). Age at diagnosis, pathological grade, histo-type, SEER stage, tumor size and surgical resection were identified as independent predictors in both OS and CSS analysis of high-grade chondrosarcoma. When stratified by histological grade, surgical resection remained the effective treatment. Strikingly, radiotherapy was determined as an independent protective factor in both OS and CSS analysis of undifferentiated (grade 4) dedifferentiated chondrosarcoma, and adjuvant radiotherapy combined surgical resection could improve both the OS and CSS of patients with undifferentiated myxoid and dedifferentiated chondrosarcoma compared with other treatment regimens. CONCLUSIONS Our study first demonstrated that adjuvant radiotherapy combined surgery could improve the survival of patients with undifferentiated myxoid and dedifferentiated chondrosarcoma. These results encourage the application of adjuvant radiotherapy for patients with high-grade chondrosarcoma and maximize the patients' outcome.

[Benign tumours and tumour-like lesions of the bone : General treatment principles]. / Benigne Tumoren und tumorähnliche Läsionen des Knochens : Allgemeine Behandlungsprinzipien.

BACKGROUND: Benign bone lesions are much more common than malignant lesions. Some benign bone tumors have a characteristic and typical radiographic appearance, while others are more challenging. Therapy of benign bone tumors differs greatly. While the majority of benign bone tumors do not require surgical therapy, other specific lesions, e. g. aneurysmal bone cysts or giant cell tumors (GCT) of the bone require surgery due to their locally aggressive behavior. DIAGNOSTICS: The major challenge for the radiologist and/or pathologist is the differentiation between a benign and low-grade malignant lesion (e. g. enchondroma versus low-grade chondrosarcoma) for which all available clinical and radiographic information is mandatory. Therefore, surgical therapy is rather more often performed than necessary due to uncertainty in many cases. THERAPY: Novel systemic therapies are available for fibrous dysplasia and GCT of the bone: Fibrous dysplasia can be treated with bisphosphonates, and GCT responds to denosumab. In fact, denosumab has been approved for the treatment of irresectable GCT. Osteoid osteoma is fairly easy to recognize and also to treat given the characteristic clinical presentation and rapid and effective response to local therapy (possible as percutaneous thermo-/laser ablation). In summary, several therapeutic options exist for benign bone tumors, and the choice depends upon the tendency/risk of local recurrence, the rate of surgical complications, options for defect reconstruction, postoperative functional deficits, and specific patient characteristics.

[Conventional radiological diagnosis of benign none neoplasms]. / Konventionell-radiologische Diagnose von gutartigen Knochentumoren.

BACKGROUND: Benign bone tumors are of special clinical importance because they might be confused with malignant bone tumors. OBJECTIVES: The aim of this article it to present the characteristics of benign bone tumors. The focus is orientated towards conventional x­ray as the essential pillar for primary diagnosis. Consequently, the description of signal intensities of benign bone tumors in magnetic resonance images or less helpful clues like male-female ratios are deliberately omitted. RESULTS: The classification of bone tumors introduced by Lodwick allows the identification of benign growth patterns. Growth patterns will not help, for example, in case of dedifferentiation of benign chondroid tumors towards chondrosarcomas. Therefore, each diagnosis has to incorporate the patient's clinical scenario. Furthermore, benign bone tumors might also cause aggressive growth patterns. Tumors classified as Lodwick Ic or higher should not be automatically regarded as malignant. Naturally, further clarification is mandatory for these tumors. CONCLUSIONS: Differentiation between definitely benign bone tumors and those which need further work up is a critical diagnostic step. In the majority of cases, this is possible based on the appearance in conventional x­ray images. In case of possibly malignant lesions, both the patient's symptoms and the x­ray morphology have to be considered by orthopedic surgeons, pathologists, and radiologists to determine the optimal diagnostic strategy.

The biology and management of cartilaginous tumors: a role for targeting isocitrate dehydrogenase.

Chondrosarcomas are rare mesenchymal neoplasms defined by the production of abnormal cartilaginous matrix. Conventional chondrosarcoma is the most common histology. The management of primary conventional chondrosarcoma generally is surgical with the possible addition of radiation therapy. Treatment of conventional chondrosarcoma is problematic in unresectable or metastatic disease because the tumors tend to be resistant to standard sarcoma chemotherapy regimens. Previous attempts at targeted therapy, including inhibitors of Hedgehog signaling, the mTOR pathway, and platelet-derived growth factor receptor (PDGFR) have been largely disappointing. However, heterozygous mutations in isocitrate dehydrogenase (IDH) enzymes recently have been identified in chondrogenic neoplasms, with mutations reported in approximately 87% of benign enchondromas, 70% of conventional chondrosarcomas, and 54% of dedifferentiated chondrosarcomas. The normal IDH protein continues to produce alpha-ketoglutarate (alpha-KG) whereas the mutant IDH protein converts KG to the oncometabolite 2-hydroxyglutarate (2-HG). Clinical trials of novel IDH inhibitors are ongoing, with evidence of early activity in IDH-mutant leukemias. IDH inhibitors show antitumor effects against IDH-mutant chondrosarcoma cell lines, supporting the inclusion of patients with chondrosarcoma with IDH mutations on IDH inhibitor clinical trials for solid tumors. Targeting IDH mutations may offer hope of a novel antineoplastic strategy not only for patients with chondrosarcomas, but also for other solid tumors with aberrant IDH activity.

Dedifferentiated chondrosarcoma: an aggressive variant of chondrosarcoma.

Dedifferentiated chondrosarcomas are a rare and aggressive subtype of chondrosarcoma with a bimorphic pattern on histopathology. Rib is a rare site of dedifferentiated chondrosarcoma. Diagnosis of this subtype preoperatively can be challenging. Treatment options for dedifferentiated chondrosarcoma are limited because they are chemoresistant, and therefore adequate surgery forms the main stay of treatment. We present our experience with a dedifferentiated chondrosarcoma of the rib, and discuss the management of this rare entity.

Chapter 10: Sinonasal malignancies.

Malignant tumors of the sinonasal tract are uncommon tumors of the head and neck. Patients often present in the later years of life with unilateral symptoms and potential involvement of nearby structures such as the orbit, brain, or cranial nerves. Presenting symptoms are similar to patients suffering from inflammatory sinonasal disease and thus early diagnosis relies heavily on a high clinical suspicion. There are established risk factors based on exposure to the by-products of woodworking, metal, textile, and leather industries. Sinonasal malignancies are generally divided into those of epithelial origin (squamous cell carcinoma, adenocarcinoma, and adenoid cystic carcinoma) and nonepithelial origin (olfactory neuroblastoma, chondrosarcoma, and mucosal melanoma). Accurate histopathology confirmation and staging of the tumor is critical prior to making treatment decisions. Both computed tomography and magnetic resonance imaging are required to accurately determine the extent of local disease. Treatment is based on multimodality therapy, primarily surgical excision, and postoperative radiotherapy. This article reviews the classification of malignant tumors of the paranasal sinuses, their clinical presentation, relevant diagnostic investigations, and the principals of therapy and management.

[Histological classification of soft tissue tumors and staging according to the TNM system]. / Histologische Klassifikation von Weichgewebstumoren und Stadieneinteilung gemäß TNM-System.

The classification of soft tissue tumors is based on their resemblance to normal non-neoplastic tissues and provides an indication of how the tumor will behave in the further disease course. The current article presents the principles to be considered when classifying tumors into categories and discusses additional findings to be taken into account in the diagnosis. The importance of considering combinations of findings when classifying a tumor is underscored; individual (in particular immunohistochemical) findings can be misleading. A statement on the grade of malignancy of a soft tissue tumor requires its identification as a known entity, otherwise incorrect prediction of its biological behaviour is possible. The category of "intermediate malignancy" has been added to the categories of "benign" and "malignant", whereby locally aggressive and incidentally metastasizing tumors have been included in this new category. The staging of soft tissue tumors according to the TNM system is explained, emphasizing that one important feature compared with carcinomas is the inclusion of depth localisation and grade of malignancy.

Hierarchical clustering of flow cytometry data for the study of conventional central chondrosarcoma.

We have investigated the use of hierarchical clustering of flow cytometry data to classify samples of conventional central chondrosarcoma, a malignant cartilage forming tumor of uncertain cellular origin, according to similarities with surface marker profiles of several known cell types. Human primary chondrosarcoma cells, articular chondrocytes, mesenchymal stem cells, fibroblasts, and a panel of tumor cell lines from chondrocytic or epithelial origin were clustered based on the expression profile of eleven surface markers. For clustering, eight hierarchical clustering algorithms, three distance metrics, as well as several approaches for data preprocessing, including multivariate outlier detection, logarithmic transformation, and z-score normalization, were systematically evaluated. By selecting clustering approaches shown to give reproducible results for cluster recovery of known cell types, primary conventional central chondrosacoma cells could be grouped in two main clusters with distinctive marker expression signatures: one group clustering together with mesenchymal stem cells (CD49b-high/CD10-low/CD221-high) and a second group clustering close to fibroblasts (CD49b-low/CD10-high/CD221-low). Hierarchical clustering also revealed substantial differences between primary conventional central chondrosarcoma cells and established chondrosarcoma cell lines, with the latter not only segregating apart from primary tumor cells and normal tissue cells, but clustering together with cell lines from epithelial lineage. Our study provides a foundation for the use of hierarchical clustering applied to flow cytometry data as a powerful tool to classify samples according to marker expression patterns, which could lead to uncover new cancer subtypes.

Differentiating high-grade from low-grade chondrosarcoma with MR imaging.

The purpose of the study was to evaluate theMR imaging features that differentiate between low-grade chondrosarcoma (LGCS) and high-grade chondrosarcoma (HGCS) and to determine the most reliable predictors for differentiation. MR images of 42 pathologically proven chondrosarcomas (28 LGCS and 14 HGCS) were retrospectively reviewed. There were 13 male and 29 female patients with an age range of 23­72 years (average age 51 years). On MR images, signal intensity, specific morphological characteristics including entrapped fat, internal lobular architecture, and outer lobular margin, soft tissue mass formation and contrast enhancement pattern were analysed. MR imaging features used to identify LGCS and HGCS were compared using univariate analysis and multivariate stepwise logistic regression analysis. On T1-weighted images, a central area of high signal intensity, which was not seen in LGCS, was frequently observed in HGCS (n = 5, 36%) (p<0.01). Entrapped fat within the tumour was commonly seen in LGCS (n = 26, 93%), but not in HGCS (n = 1, 4%) (p<0.01). LGCS more commonly (n = 24, 86%) preserved the characteristic internal lobular structures within the tumour than HGCSs (n = 4, 29%) (p<0.01). Soft tissue formation was more frequently observed in HGCS (n = 11, 79%) than in LGCS (n = 1, 4%) (p<0.01). On gadolinium-enhanced images, large central nonenhancing areas were exhibited in only two (7.1%) of LGCS, while HGCS frequently (n = 9, 64%) had a central nonenhancing portion (p<0.01). Results of multivariate stepwise logistic regression analysis showed that soft tissue formation and entrapped fat within the tumour were the variables that could be used to independently differentiate LGCS from HGCS. There were several MR imaging features of chondrosarcoma that could be helpful in distinguishing HGCS from LGCS.Among them, soft tissue mass formation favoured the diagnosis of HGCS, and entrapped fat within the tumour was highly indicative of LGCS.

Assessment of interobserver variability and histologic parameters to improve reliability in classification and grading of central cartilaginous tumors.

The distinction between benign and malignant cartilaginous tumors of bone is one of the most difficult subjects in surgical pathology. The grading of chondrosarcoma also seems to vary considerably among pathologists. However, clinical management differs. The purpose of this study was (1) to investigate interobserver variability in histological diagnosis and grading of central cartilaginous tumors and (2) to assess the diagnostic value of defined histologic parameters in differentiating enchondroma and central grade I chondrosarcoma. The interobserver variability was assessed using a set of 16 cases evaluated by 18 specialized pathologists. Subsequently, 20 enchondromas and 37 central grade I chondrosarcomas diagnosed in a multidisciplinary team with full clinical, radiologic, and pathologic data available with 10 years of follow-up were collected. Cytologic and tissue-architectural features were assessed to find an optimal set of parameters to differentiate enchondroma from central grade I chondrosarcoma. We demonstrate considerable variation in the histologic assessment of cartilaginous tumors (weighted kappa=0.78). The distinction between enchondroma and grade I chondrosarcoma was shown to be the most disconcordant (kappa coefficient=0.54), and also the differentiation between grade I and grade II chondrosarcoma was subjected to variation (kappa coefficient=0.80). The application of a combination of 5 parameters (high cellularity, presence of host bone entrapment, open chromatin, mucoid matrix quality, and age above 45 y) allowed optimal differentiation between enchondromas and central grade I chondrosarcomas. With a classification tree based on 2 parameters (mucoid matrix degeneration more than 20% and/or host bone entrapment present), 54 of the 57 (94.7%) cases were assessed correctly (sensitivity 95% and specificity 95%). Our study confirms the low reliability of the diagnosis and grading of central chondrosarcoma. However, these classifications guide therapeutic decision making in daily practice. Therefore, we propose a classification model that, combined with a tailored radiologic assessment, may improve reliability of the diagnosis of cartilaginous tumors.

[Cartilage tumors of the skeleton]. / Chondrogene Tumoren des Skeletts.

Although the spectrum of benign and malignant cartilaginous bone tumors is extremely wide, a distinct diagnosis, even from small biopsy specimens, is almost always possible if radiological findings, age, clinical data, and localization within the skeleton as well as within the bone are considered. With limitations, this also holds true for distinguishing enchondromas from low-grade chondrosarcomas; however, extensive experience in multidisciplinary bone tumor diagnosis is required. In single cases, immunohistochemical findings may be helpful in the differential diagnosis if they are integrated into the context of all other findings. Because of treatment-related or prognosis-related consequences, collaboration with a reference center is recommended.

Effectiveness of radiotherapy in myxoid sarcomas is associated with a dense vascular pattern.

PURPOSE: Surgery and adjuvant radiotherapy (RT) have long been the standard treatment for most deep-seated sarcomas; however, since the randomized trial from the National Cancer Institute of Canada, which described similar local control for pre- vs. postoperative RT, both modalities are now widely accepted. As a group, sarcomas are classified as radiation resistant. The subgroup of myxoid liposarcoma (MLS), a sarcoma with a typical vascular crow's feet pattern, is highly radiosensitive, but a mechanism for this phenomenon is unknown. Here we describe our results with preoperative RT and propose a mechanism explaining the high sensitivity based on the distinctive vascularization pattern of MLS. METHODS AND MATERIALS: Between 2002 and 2006, 31 sarcoma patients, including 10 with MLS, underwent preoperative RT at our institute. Resected specimens were histologically evaluated, focusing on classification, grade, and vascularization patterns. RESULTS: Twenty sarcomas showed more than 80% pathologic response after preoperative RT. A pathologic complete response was found in all "pure" MLS specimens after preoperative RT (n = 8). There were no pathologic complete responses in the remaining sarcoma patients (n = 23), although 12 showed 80% to 90% pathologic response. In contrast to the remaining RT-resistant sarcomas, the highly responding specimens contained branching vasculature, partial thrombus formation and inflammation of medium sized arterioles, similar to the vascular changes in MLS. CONCLUSIONS: Both MLS and sarcomas with MLS-like vasculature are highly radiosensitive. Radiation sensitivity may be explained by changes in medium-sized arterioles, obstructing the specific crow's feet vascularization and inducing hypoxia with secondary tumor cell death.

[Osteochondrosarcoma: clinical and morphological comparisons].

A total of 109 patients with chondrosarcoma were operated on in 2005-2007. Classical primary chondrosarcoma was verified in 77 cases; secondary and periosteal chondrosarcomas were confirmed in 28 and 4 patients, respectively. By analyzing their findings and the data available in the literature, the authors considered the current problems in the classification and diagnosis of the most common types of cartilaginous malignancies. New techniques, including cytogenetic assay, significantly alleviate this problem. However, the most precise cytogenetic assays are expensive and not always accessible for usual oncological care. The principal criteria in practice are a clinical picture, the results of radiation studies, and the standard histological method that establishes the differentiation of chondrosarcoma, the extent of a process, and the specific features of tumor growth. Immunohistochemical assay are of no crucial importance. In some cases, fine-needle biopsy may provide useful information to make a decision on treatment policy.

Molecular pathology of chondroid neoplasms: part 2, malignant lesions.

This is the second part of a two-part review presenting an overview of the molecular findings associated with both benign and malignant chondroid neoplasms. The first part presented a brief review of modern methods in molecular pathology, along with a review of the cytogenetic and molecular genetic findings in benign chondroid neoplasms. This second part reviews the cytogenetic and molecular genetic findings in malignant chondroid neoplasms. Clinical aspects of the various lesions are briefly discussed, and each tumor is illustrated with representative radiographic and pathologic images.

Skull base chondrosarcoma originating from the petroclival junction.

OBJECTIVE: To define the presentation of patients with skull base chondrosarcoma, to elucidate surgical strategies, and to identify the role of postoperative radiotherapy. STUDY DESIGN: Retrospective review. SETTING: Tertiary referral center. PATIENTS: All patients (n = 33) with skull base chondrosarcoma managed at our institution. The average follow-up time was 7.7 years (range, 0-20 years). MAIN OUTCOME MEASURES: Tumor location, presenting symptoms, presence of residual or recurrent tumor, and mortality. RESULTS: The most common tumor location was the petroclival junction (n = 29). Common presenting symptoms were diplopia (48%) and headache (45%). Surgical approaches included retrosigmoid, transtemporal, transfacial, and frontotemporal craniotomies. Biopsy only was performed in four patients, subtotal resection in 19 patients, and total resection in nine patients. Most patients received postoperative radiotherapy (82%). Follow-up revealed residual, stable disease in 28% of patients and recurrent disease in 24% of patients. The mean time to recurrence was 3.0 +/- 2.8 years. The lack of postoperative radiation was significantly correlated with an increased risk of recurrence (odds ratio, 28; p = 0.007) but incomplete tumor resection was not (p = 0.6). Life-table analysis revealed that the 5-year survival rate was 85% and the 10-year survival rate was 77%. Five patients died; four of the deaths attributable to recurrent disease. CONCLUSION: The characteristic growth pattern of skull base chondrosarcoma is tumor eroding the petroclival junction. Current therapeutic strategy is resection through an extradural subtemporal craniotomy with removal of the petrous apex and clivus. Radical resection of uninvolved structures is often not necessary. Nonetheless, gross total removal is often achievable. Postoperative radiotherapy reduces the chance of tumor recurrence.