Recent advances in molecular profiling of bone and soft tissue tumors.

The molecular characterization of soft tissue and bone tumors is a rapidly evolving field that has changed the perspective of how these tumors are diagnosed today. Morphology and clinico-radiological context still represent the cornerstone of diagnostic considerations but are increasingly complemented by molecular data that aid in objectifying and confirming the classification. The spectrum of analyses comprises mutation or gene fusion specific immunohistochemical antibodies, fluorescence in situ hybridization, DNA and RNA sequencing as well as CpG methylation profiling. This article provides an overview of which tools are presently available to characterize bone and soft tissue neoplasms molecularly, what limitations should be considered, and what conclusions can be drawn from the individual findings.

[Odontogenic tumours and bone tumours of the jaw : Changes in the new WHO classification]. / Odontogene Tumoren und Knochentumoren der Kieferregion : Änderungen der neuen WHO-Klassifikation.

At the beginning of 2017, the fourth edition of the WHO Classification of Head and Neck Tumours was published, 12 years after the previous version. Notably, various changes introduced in the third edition have been revised so in some aspects the current classification has more similarities to the second edition of 1992 than to the third edition. A central goal of the editors was to create a classification that can be used worldwide. Molecular findings have therefore been included and updated but are not mandatory for establishing a diagnosis. This article discusses and comments on the most important changes implemented in the classification of gnathic lesions.

[Pathogenesis and genetics of osteosarcoma : Current concepts and developments]. / Pathogenese und genetischer Hintergrund des Osteosarkoms : Aktuelle Konzepte und Entwicklungen.

Osteosarcomas are genetically complex tumours for which the cell of origin and the molecular pathogenesis are still poorly understood. Despite intensive multimodal treatment protocols only two thirds of patients currently survive the disease which is at least partly due to the early occurring chromosomal instability resulting in marked inter- and intratumoral heterogeneity. This review article outlines the current state of osteosarcoma research with a particular focus on exome- and genome-wide sequencing analyses and potential impacts on new therapeutic opportunities.

[Chondroblastoma]. / Chondroblastom.

Chondroblastomas are very rare benign primary bone tumors occurring preferentially in the epiphyses or apophyses of long bones in children and adolescents. In most cases the typical histological and imaging findings lead to a correct diagnosis that may be substantiated by demonstrating the highly specific point mutation in the H3F3B gene (p.K36M), either by sequencing or immunohistochemistry. Recurrences occur in 5-15% of cases, postsurgical metastatic deposits to the lungs are very rare (<1%). Histologically "malignant" chondroblastomas have been reported as single case reports. The treatment of choice is a thorough curettage, also in the case of local relapses.

[Cystic lesions of the jaws]. / Zystische Kieferläsionen.

Cystic lesions of the jaws comprise a spectrum of inflammatory, developmental and neoplastic changes that can clinically appear strikingly similar. Squamous cell metaplasia due to superinfection can further blur the histologic hallmarks of the individual lesions. In this article an overview of the most important differential diagnoses and the novelties of the latest World Health Organisation (WHO) classification on head and neck tumours released in early 2017 is provided. In contrast to the previous edition, odontogenic cysts have been re-introduced and several changes in terminology and taxonomy have been complemented.

[Hereditary bone tumors]. / Hereditäre Knochentumoren.

Hereditary bone tumors are rare and result from mutations affecting cell cycle regulation (e.g. retinoblastoma syndrome/RB1 and Li-Fraumeni syndrome/TP53, Gardner syndrome/APC), energy metabolism (enchondromatosis/IDH1/2), complex signaling cascades (multiple hereditary exostoses/EXT1/2) and DNA integrity (Rothmund-Thomson/RECQL4, Werner/WRN and Bloom syndromes/BLM). The majority of syndromes are incompletely understood and can lead to multiple benign tumors, of which some might undergo secondary malignant transformation over time (enchondromatosis: enchondromas, multiple hereditary exostoses: osteochondromas, Gardner syndrome: osteomas) or bone sarcomas, primarily osteosarcomas as primary (Li-Fraumeni, Rothmund-Thomson, Werner and Bloom syndromes) or secondary manifestation (retinoblastoma syndrome) of the disease. Some syndromes additionally predispose to the development of a variety of other malignant tumors during life. Compared to sporadically occurring tumors, syndrome-related neoplasms can differ in the time of manifestation, site and histology, which can help in recognizing a specific tumor predisposition syndrome.

[The clonal evolution of osteosarcomas]. / Die klonale Evolution des Osteosarkoms.

Osteosarcomas are highly aggressive bone tumors that mainly occur in the metaphyses of long bones in children and adolescents. Genetically, they are characterized by complex structural and numerical aberrations with large intra- and interindividual variations which hamper the identification of the initiating and driving events. Sequencing and copy number analyses in a study of 123 pretherapeutic osteosarcoma samples identified mutations in 14 genes as the potential main drivers. Although almost half of all osteosarcomas could be attributed to mutations in TP53 and RB1, no single driver gene could be found that was clearly responsible for the majority of tumors. There were also no unequivocal correlations between single aberrations and clinicopathological parameters; however, when looking at the mutation signatures, a striking resemblance to BRCA-deficient breast cancer was evident in the majority of osteosarcoma profiles. We therefore focused our interest on genes involved in homologous recombination repair and applied different algorithms that have been shown in the literature to be indicators for functional impairment in these signaling cascades. Indeed, >80 % of osteosarcomas showed signatures similar to BRCA-deficient tumors and in osteosarcoma cell lines a response to poly(ADP-ribose) polymerase (PARP) inhibitors could be demonstrated. Our findings thus imply that multiple oncogenic pathways can converge and lead to chromosomal instability during osteosarcoma evolution resulting in the acquisition of BRCA-like traits, which might be of potential therapeutic relevance.

Aneurysmal bone cyst (ABC) : treatment options and proposal of a follow-up regime.

The aim of this study was to describe treatment -options and develop a follow-up regime for the -aneurysmal bone cyst, a neoplastic bone lesion with a noticeable recurrence rate. Reports of 28 patients and a mean follow-up of 42.2 months treated multidisciplinary were analysed. Data were complemented by a literature review including 790 patients. Patient age was from seven to 57 years, in line with the literature (1-69 years). Lesions most frequently affect long bones, spine and pelvis ; pain is the most common symptom. Treatment modalities vary, recurrences -occurred in 26.1% in our series, rates ranged from 0-60% in the literature, with the vast majority within 2 years. With regard to the findings we propose, irrespective of treatment, a follow-up regime including clinical survey and imaging, best with MRI, at 3 months, 6 months and at half-yearly intervals within the first two and yearly within the third to fifth year.

[Pathological assessment of bone sarcomas]. / Pathologische Begutachtung von Knochensarkomen.

Bone tumors are very rare. Diagnosis and treatment is an interdisciplinary task for experienced radiologists, pathologist, and surgeons that is ideally performed in specialized centers. For optimal processing of bone specimens, basic laboratory equipment and special techniques are required. The cornerstone of the histological diagnosis remains H&E staining, supplemented by special stains, immunohistochemistry, and molecular techniques. For an appropriate diagnosis, data on clinical history, age, location, topography within bone, and imaging are required. Major differences between histological and radiological diagnosis have to be clarified before starting treatment (e.g., by involving a reference registry).

Low-grade fibromyxoid sarcoma and sclerosing epithelioid fibrosarcoma, outcome of advanced disease: retrospective study from the Ultra-Rare Sarcoma Working Group.

BACKGROUND: To present findings from a retrospective study conducted by the Ultra-Rare Sarcoma Working Group on metastatic low-grade fibromyxoid sarcoma (LGFMS), sclerosing epithelioid fibrosarcoma (SEF), and hybrid (H)-LGFMS/SEF across 28 global centres. METHODS: Patients treated at participating institutions from January 2000 to September 2022 were retrospectively selected. Diagnosis was confirmed by expert pathologists. Primary endpoint was progression-free survival (PFS-1) from metastasis detection to first progression or death. PFS-2 was calculated from therapy initiation. RESULTS: A total of 101 patients were identified (32 LGFMS, 50 SEF, 19 H-LGFMS/SEF). Median (m) follow-up was 62.1 months. mPFS-1 was 28.7, 11.8, and 20.3 months for LGFMS, SEF, and H-LGFMS/SEF, respectively. mOS was 145.8, 41.9, and 113.5 months, respectively. Treatments included anthracycline-based chemotherapy, gemcitabine-based chemotherapy (G), pazopanib, trabectedin, others. mPFS-2 was: 20.1, 5.5, and 3.5 months in H-LGFMS/SEF, SEF, and LGFMS, respectively, with anthracyclines; 19.5, 7.7, and 6.9 months in LGFMS, SEF, and H-LGFMS/SEF, respectively, with pazopanib; 12.0, 9.7, and 3.1 months in H-LGFMS/SEF, LGFMS, and SEF, respectively. Occasional responses occurred with ifosfamide/oral cyclophosphamide, and prolonged stable disease with immune checkpoint inhibitors. CONCLUSIONS: In this series, the largest available, metastatic LGFMS, SEF, and H-LGFMS/SEF showed different courses. Systemic agents have modest efficacy, informing future trials of novel agents for these tumours.

[Osteochondroma and multiple osteochondromas: recommendations on the diagnostics and follow-up with special consideration to the occurrence of secondary chondrosarcoma]. / Osteochondrom und multiple Osteochondrome : Empfehlungen zur Diagnostik und Vorsorge unter besonderer Berücksichtigung des Auftretens sekundärer Chondrosarkome.

PURPOSE: Osteochondroma represents the most common form of benign bone tumor. Clinical manifestations include deformity of bone, compression of surrounding tissue and vascular or neurological compromise. Osteochondromas may be solitary (solitary osteochondroma, SO) or multiple (multiple osteochondromas MO). Recurrence after surgery is a known problem especially in MO and malignant transformation is rare but more common in MO than in solitary cases. Reliable recommendations regarding diagnostics and clinical follow-up are currently lacking. PATIENTS AND METHODS: A comprehensive literature review and a review of own patient files with SO/MO treated between 2000 and 2011 in this hospital were performed. The age of patients at diagnosis, tumor localization, clinical aspects, recurrence and the risk of malignant transformation in secondary (i.e. epiexostotic) chondrosarcoma were analyzed. The follow-up including patients who received surgery ranged between 2 and 127 months for patients with SO and between 2 and 84 months for MO. RESULTS: A total of 39 patients with SO from this hospital were included in the study. Out of 36 patients who received surgery 3 recurrences were registered after an average time of 62 months. In addition, 11 patients with MO were identified and all received surgery. In 5 out of 11 cases recurrences occurred after an average time of 20.6 months. Secondary chondrosarcomas were not recorded in this series. According to the literature an increased risk of malignant transformation was found for osteochondromas of the axial skeleton, in the proximal aspect of the extremities, as well as for recurrent tumors and for MO. Pain and/or increase in size of lesions after skeletal maturation were the most common clinical signs of transformation. There was a wide time interval between the initial diagnosis and the development of secondary chondrosarcoma. In MO secondary chondrosarcoma has been described before skeletal maturity. CONCLUSIONS: The risk of malignant transformation of SO is generally low. Axial lesions as well as recurrent osteochondromas and MO seem to have an increased risk of malignant transformation. The follow-up, requiring sufficient primary diagnostics, includes regular self-control and can usually be clinically carried out in more peripherally located lesions but in certain cases supplementary X-ray imaging is needed. In cases of anatomical regions which are more difficult to access manually, follow-up examination by magnetic resonance imaging (MRI) is the method of choice. Especially MO patients seem to benefit from long-term follow-up: when the tumor is located in the trunk and in (proximal) long bones MRI or whole-body MRI, respectively, should be performed once a year after skeletal maturity because of the higher risk of malignant transformation in these patients.

[Molecular characterization of osteosarcomas]. / Molekulare Charakterisierung von Osteosarkomen.

Osteosarcomas are rare with an estimated incidence of 5-6 cases per one million inhabitants per year. As the prognosis has not improved significantly over the last 30 years and more than 30 % of patients still die of the disease a better understanding of the molecular tumorigenesis is urgently needed to identify prognostic and predictive biomarkers as well as potential therapeutic targets. Using genome-wide SNP chip analyses we were able to detect a genetic signature enabling a prognostic prediction of patients already at the time of initial diagnosis. Furthermore, we found the microRNA cluster 17-92 to be constitutively overexpressed in osteosarcomas. The microRNAs included here are intermingled in a complex network of several oncogenes and tumor suppressors that have been described to be deregulated in osteosarcomas. Therefore, the microRNA cluster 17-92 could represent a central regulator in the development of osteosarcomas.

[Revised consensus classification. Histopathological classification of diseases associated with joint endoprostheses]. / Erweiterte Konsensusklassifikation. Histopathologische Klassifikation von Gelenkendoprothesen-assoziierten Erkrankungen.

The revised classification of the periprosthetic membrane (synovial-like interface membrane SLIM) encompasses all pathological alterations which can occur as a result of endoprosthetic replacement of major joints and lead to a reduction in durability of prostheses. This also includes the established consensus classification of SLIM by which aseptic and septic prosthetic loosening can be subdivided into four histological types and histopathological criteria for additional pathologies: endoprosthesis-associated arthrofibrosis, immunological/allergic alterations and osseous pathologies. This revision represents the foundation for the histopathological diagnostics of the total spectrum of diseases associated with joint prostheses, is a suitable basis for a standardized diagnostic procedure and etiological clarification of endoprosthesis failure and also as a data standard for endprosthesis registers, in particular for registers based on routine data (e.g. German endoprosthesis register).

High STEAP1 expression is associated with improved outcome of Ewing's sarcoma patients.

BACKGROUND: Ewing's sarcoma (ES) is the second most common bone or soft-tissue sarcoma in childhood and adolescence and features a high propensity to metastasize. The six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is a membrane-bound mesenchymal stem cell marker highly expressed in ES. Here, we investigated the role of STEAP1 as an immunohistological marker for outcome prediction in patients with ES. PATIENTS AND METHODS: Membranous STEAP1 immunoreactivity was analyzed using immunohistochemistry in 114 primary pre-chemotherapy ES of patients diagnosed from 1983 to 2010 and compared with clinical parameters and patient outcome. Median follow-up was 3.85 years (range 0.43-17.51). RESULTS: A total of 62.3% of the ES samples displayed detectable STEAP1 expression with predominant localization of the protein at the plasma membrane. High membranous STEAP1 immunoreactivity was found in 53.5%, which correlated with better overall survival (P=0.021). Accordingly, no or low membranous STEAP1 expression was identified as an independent risk factor in multivariate analysis (hazard ratio 2.65, P=0.036). CONCLUSION: High membranous STEAP1 expression predicts improved outcome and may help to define a specific subgroup of ES patients, who might benefit from adapted therapy regimens.

[Infectious bone diseases]. / Infektiöse Knochenerkrankungen.

Bacterial infection of the bone is a severe disease with complications, potentially including long-term physical disability. The diagnosis and therapy of osteomyelitis include several elements: histopathology, microbiology, radiologic imagining, as well as antibiotic and surgical therapy. Histopathologists differentiate between acute osteomyelitis (infiltration of cancellous bone with neutrophil granulocytes); specific osteomyelitis (epithelioid-like granulomatous inflammation, tuberculosis, mycotic infections); primary/secondary chronic osteomyelitis (lymphocytic infiltration); and special forms of chronic osteomyelitis (varying histomorphology, Brodie abscess, SAPHO syndrome). Another important task in the histopathological diagnosis of inflammatory bone diseases is to differentiate osteomyelitis from malignant entities (sarcoma, lymphoma). Therefore, biopsy samples should be of sufficient size for safe diagnosis. Clinical information and imaging as well as interdisciplinary teamwork between radiologists, microbiologists, orthopedic surgeons and pathologists is mandatory to verify these diagnoses.

[Hereditary bone tumors]. / Familiäre Tumorerkrankungen im Knochen.

Familial diseases leading to bone tumor formation are rare. They are mainly caused by genetic alterations of cell cycle constituent genes, such as retinoblastoma syndrome (RB1) and Li-Fraumeni syndrome (p53), of genes involved in growth-regulating transcriptional cascades, such as enchondromatosis (PTHR1) and multiple hereditary exostoses (EXT1, EXT2) or of genes maintaining chromosomal stability, such as Rothmund-Thomson (RECQL4), Werner (WRN) and Bloom syndromes (BLM). This leads to multiple benign bone tumors, which may undergo secondary malignant transformation (enchondromatosis: enchondromas, multiple hereditary exostoses: osteochondromas) or bone sarcomas, mainly osteosarcomas, such as primary (Li-Fraumeni, Rothmund-Thomson, Werner and Bloom syndromes) or secondary manifestations (retinoblastoma syndrome) of the underlying disease. Some of these lesions also carry an increased risk for developing additional malignant diseases. In contrast to sporadically occurring similar tumors, differences in manifestation in time, topography or histology may be present which can aid in the correct recognition of the underlying syndrome.

Quantitative signal intensity ratios to distinguish between subfascial lipoma and atypical lipomatous tumor/well-differentiated liposarcoma using short-tau inversion recovery (STIR) MRI.

PURPOSE: To establish simple quantitative variables at short-tau inversion recovery (STIR) magnetic resonance imaging (MRI) to identify lipomas with high specificity in patients with indeterminate subfascial lipomatous tumors. MATERIALS AND METHODS: The MRI examinations of 26 patients (14 men, 12 women; mean age 63±12.5 [SD] years; range: 40-84years) with histopathologically proven subfascial atypical lipomatous tumors/well-differentiated liposarcomas (ALT/WDLs) and those of 68 patients (32 men, 36 women; mean age, 56±13.5 [SD] years; range: 21-83years) with lipomas were retrospectively reviewed. Ratios derived from region of interest based signal intensity (SI) measurements of tumors and adjacent fat on STIR images were calculated and maximum tumor diameters were noted. Diagnostic parameter capabilities were assessed using ROC curve analysis. Interreader agreement was evaluated by calculation of intraclass correlation coefficients (ICC). RESULTS: Using a cut-off value of 1.18, STIR-SI ratios allowed discriminating between lipoma and ALT/WDL (AUC=0.88; P<0.001) yielding 93% specificity (95% CI: 77-99%) and 74% sensitivity (95% CI: 61-84%) for the diagnosis of lipoma. Interreader agreement was excellent (ICC=0.93). A significant difference in maximum tumor diameter was found between ALT/WDLs (mean: 18.1±6.0 [SD] cm; range: 5.6-33.1cm) and lipomas (mean: 9.7±5.0 [SD] cm; range: 2.9-29.1cm) (P<0.001). Using a cut-off of 11cm, maximum tumor diameter allowed discriminating between lipoma and ALT/WDLs with 92% specificity (95% CI: 75-99%) and 69% sensitivity (95% CI: 57-80%). The combination of a STIR-SI ratio<1.4 and maximum tumor diameter<11cm yielded 100% specificity (95% CI: 87-100%) and 65% sensitivity (95% CI: 54-77%) for the diagnosis of lipoma. CONCLUSION: The combination of STIR-SI ratio and maximum diameter allows discriminating between lipoma and ALT/WDL in initially indeterminate lipomatous tumors.

Surgical Outcome and Oncological Survival of Osteofibrous Dysplasia-Like and Classic Adamantinomas: An International Multicenter Study of 318 Cases.

BACKGROUND: Osteofibrous dysplasia-like adamantinoma (OFD-AD) and classic adamantinoma (AD) are rare, neoplastic diseases with only limited data supporting current treatment protocols. We believe that our retrospective multicenter cohort study is the largest analysis of patients with adamantinoma to date. The primary purpose of this study was to describe the disease characteristics and evaluate the oncological outcomes. The secondary purpose was to identify risk factors for local recurrence after surgical treatment and propose treatment guidelines. METHODS: Three hundred and eighteen confirmed cases of OFD-AD and AD for which primary treatment was carried out between 1985 and 2015 were submitted by 22 tertiary bone tumor centers. Proposed clinical risk factors for local recurrence such as size, type, and margins were analyzed using univariable and multivariate Cox regression analysis. RESULTS: Of the 318 cases, 128 were OFD-AD and 190 were AD. The mean age at diagnosis was 17 years (median, 14.5 years) for OFD-AD and 32 years (median, 28 years) for AD; 53% of the patients were female. The mean tumor size in the OFD-AD and AD groups combined was 7.8 cm, measured histologically. Sixteen percent of the patients sustained a pathological fracture prior to treatment. Local recurrence was recorded in 22% of the OFD-AD cases and 24% of the AD cases. None of the recurrences in the OFD-AD group progressed to AD. Metastatic disease was found in 18% of the AD cases and fatal disease, in 11% of the AD cases. No metastatic or fatal disease was reported in the OFD-AD group. Multivariate Cox regression analysis demonstrated that uncontaminated resection margins (hazard ratio [HR] = 0.164, 95% confidence interval [CI] = 0.092 to 0.290, p < 0.001), pathological fracture (HR = 1.968, 95% CI = 1.076 to 3.600, p = 0.028), and sex (female versus male: HR = 0.535, 95% CI = 0.300 to 0.952, p = 0.033) impacted the risk of local recurrence. CONCLUSIONS: OFD-AD and AD are parts of a disease spectrum but should be regarded as different entities. Our results support reclassification of OFD-AD into the intermediate locally aggressive category, based on the local recurrence rate of 22% and absence of metastases. In our study, metastatic disease was restricted to the AD group (an 18% rate). We advocate wide resection with uncontaminated margins including bone and involved periosteum for both OFD-AD and AD. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence.

[Warthin tumor with carcinoma: malignant transformation or metastasis?]. / Warthin-Tumor mit Karzinom: Maligne Transformation oder Metastase?

We present the unusual case of a cytologically diagnosed Warthin tumor (WT) of long standing with sudden enlargement und subsequent resection. Histologically, the diagnosis of WT was confirmed, but the tumor additionally showed diffuse infiltrates of an adenocarcinoma undergoing unrestrained growth. Warthin tumor with malignant transformation was suspected and radiological staging examinations were conducted. PET scans detected a metastasizing carcinoma of the breast, morphologically identical to the WT infiltrates. Care should always be taken when the diagnosis of malignant WT is made to exclude metastatic disease.

The Mutational Profile of Unicystic Ameloblastoma.

BRAF V600E is the most common mutation in conventional ameloblastoma (AM) of the mandible. In contrast, maxillary AMs appear to harbor more frequently RAS, FGFR2, or SMO mutations. Unicystic ameloblastoma (UAM) is considered a less aggressive variant of ameloblastoma, amenable to more conservative treatment, and classified as a distinct entity. The aim of this study was to characterize the mutation profile of UAM ( n = 39) and to compare it to conventional AM ( n = 39). The associations between mutation status and recurrence probability were also analyzed. In the mandible, 94% of UAMs (29/31, including 8/8 luminal, 6/8 intraluminal, and 15/15 mural subtypes) and 74% of AMs (28/38) revealed BRAF V600E mutations. Among the BRAF wild-type cases, 1 UAM showed a missense SMO mutation (p.L412F), whereas 2 NRAS (p.Q61R), 2 HRAS (p.Q61R), and 2 FGFR2 (p.C383R) activating mutations were identified in AM. Of the 3 maxillary UAMs, only 1 revealed a BRAF V600E mutation. Taken together, our findings demonstrate high frequency of activating BRAF V600E mutations in both UAM and AM of the mandible. In maxillary UAMs, the BRAF V600E mutation prevalence appears to be lower as was shown for AM previously. It could therefore be argued that UAM and AM are part of the spectrum of the same disease. AMs without BRAF V600E mutations were associated with an increased rate of local recurrence ( P = 0.0003), which might indicate that routine mutation testing also has an impact on prognosis.