H3F3A-mutated giant cell tumour of bone without giant cells-clinical presentation, radiology and histology of three cases.

AIMS: Giant cell tumour of bone (GCTB) is histologically defined as a lesion containing reactive giant cells and a neoplastic mononuclear cell population; in up to 92% of cases, GCTB is characterised by a specific mutation of the histone gene H3F3A. The cellular composition ranges from giant-cell-rich to giant-cell-poor. The diagnosis of GCTB can be challenging, and several other lesions need to be excluded, e.g. aneurysmal bone cysts, non-ossifying fibromas, chondroblastomas, brown tumours, and giant-cell-rich osteosarcomas. Our aim was to analyse the clinical history, imaging, molecular pathology and histology of three H3F3A-mutated bone tumours without detectable giant cells. None of the patients received denosumab therapy. METHODS AND RESULTS: Diagnostic material was obtained by curettage or resection and/or biopsy. Common histomorphological features of all three reported lesions were fibrocytic, oval cells in a background of osteoid and an absence of multinuclear giant cells as confirmed with CD68 immunohistochemistry. We used immunohistochemistry and Sanger sequencing to demonstrate positivity for the H3.3 p.G34W mutation. Differential diagnoses were systematically excluded on the basis of histomorphology, immunohistochemistry, and fluorescence in-situ hybridisation. The imaging (radiography, computed tomography, and magnetic resonance imaging) for all three cases is presented and discussed. CONCLUSIONS: We believe that these GCTBs without giant cells expand one end of the heterogeneous range of GCTB. Because of the lack of giant cells, correct diagnosis of GCTB is challenging or even impossible on histological grounds alone. In these cases, detection of the characteristic H3F3A mutation (G34W-specific antibody RM263 or sequencing) is extremely helpful for diagnosing those lesions without giant cells as giant cell tumours of bone.

H3F3A mutation in giant cell tumour of the bone is detected by immunohistochemistry using a monoclonal antibody against the G34W mutated site of the histone H3.3 variant.

AIMS: Giant cell tumour of the bone (GCTB) is a neoplasm predominantly of long bones characterized by the H3F3A mutation G34W. Conventional diagnosis is challenged by the tumour's giant cell-rich morphology, which overlaps with other giant cell-containing lesions of the bone. Recently, a monoclonal antibody specific for the H3F3A mutation has been generated. Our aim was to test this antibody on a cohort of giant cell-containing lesions. METHODS AND RESULTS: We used the antibody for analysis of 22 H3F3A-mutated GCTB, including two patients with recurrences; for comparison we analysed a cohort of 36 H3F3A wild-type giant cell-rich lesions of the bone and soft tissue, containing one brown tumour, six aneurysmal bone cysts (ABC), six chondroblastomas, five non-ossifying-fibromas, two fibrous dysplasias, nine tenosynovial giant cell tumours, one giant cell-rich sarcoma and six osteosarcomas. Furthermore, among the 22 mutated cases, we included one GCTB with two recurrences and lung metastases; the patient was treated with the anti-receptor activator of nuclear factor κB (RANK) ligand denosumab. We show that all 22 H3F3A-mutated GCTB display strong nuclear H3.3 G34W staining in the neoplastic component, while the osteoclastic giant cells are negative. 36 H3F3A wild-type lesions are negative. The GCTB treated with denosumab revealed a reduction in the H3.3 G34W-positive tumour cells and a decrease in osteoclastic giant cells accompanied by matrix and osteoid formation. CONCLUSIONS: We conclude that positive H3.3 G34W staining is a specific and sensitive method for detection of H3F3A-mutated GCTB. Denosumab treatment leads to a pathomorphosis of the lesion characterized by matrix and osteoid producing H3.3 G34W-negative stromal cells.

Metabolic alkalosis, acute renal failure and epileptic seizures as unusual manifestations of an upside-down stomach.

Upside-down stomach represents a critical and rare manifestation of hiatal hernias. Here we report on a 60-year-old male patient who was admitted to our hospital with epileptic seizures and dehydration. Laboratory tests revealed severe metabolic alkalosis (pH 7.56) with low potassium (2.7 mmol/l), hypochloremia (<60 mmol/l), increased hematocrit (53%) and high levels of serum creatinine (651 µmol/l). Based on a history of recurrent vomiting, gastroscopy and computed tomography were performed. Both diagnostics showed an upside-down stomach with signs of incarceration. Upon infusion of sodium chloride 0.9%, acid-base state, electrolyte balance and renal function became improved. Subsequently, the patient was referred to the department of surgery for hiatoplasty with fundoplication. This case report highlights severe metabolic and neurological disorders as unusual and life-threatening complications of an upside-down stomach.

The role of dynamic, contrast-enhanced MRI in differentiating lung tumor subtypes.

The aim was to correlate dynamic magnetic resonance imaging perfusion parameters of pulmonary tumors with histological tumor classification. Eighty-six patients with lung cancer were examined. A differentiation of non-small cell lung cancer vs. small cell lung cancer was possible with the parameters tumor necrosis, maximum contrast upslope, and the time until the maximum contrast upslope was reached. The beginning of a relevant contrast uptake, the mean time to peak and the time until the maximum contrast upslope was reached allowed a differentiation between squamous cell carcinoma and adenocarcinoma.