Brown tumours can be difficult to differentiate from giant cell tumours of bone (GCTB) as both tumours consist of mononuclear stromal cells with large multinucleated giant cells on histology (1). Calcium and parathyroid hormone (PTH) levels can be useful indicators of the underlying pathology but can occasionally be misleading.
A 71-year-old female was incidentally found to have an elevated adjusted serum calcium of 2.59mmol/L with a PTH level of 14pmol/L (1.6-6.9pmol/L) in 2017 and reviewed by endocrinology. She had a background of Parkinson’s disease diagnosed in 2018 and a patella fracture following a fall at home in 2010 requiring surgery. A hysterectomy and bilateral salpingo-oophorectomy for severe endometriosis was performed at age 34 with subsequent hormone replacement therapy for less than ten years. In 2018 her plasma 25-hydroxyvitamin D was 47nmol/L (50-150nmol/L), and was adequate on repeat testing after supplementation, normal liver function tests and 24-hour urine calcium creatinine ratio of 0.018. She sustained a plain film proven fracture of her left distal radius and ulna in 2019 after falling from a standing height, which was reduced and casted. Despite this, she suffered ongoing left wrist deformity and swelling.
DEXA bone density scan in February 2020 showed a left forearm T-score of -3.4, left hip T score -0.9, L1-L4 T score of 0.0, Garvan score of 11% ten-year hip fracture risk and 39% of any osteoporotic fracture risk. Nuclear medicine parathyroid uptake scan in October 2020 revealed uptake consistent with a right superior parathyroid adenoma. Neck ultrasound was non-diagnostic for an adenoma. She was referred to the endocrine surgeons in April 2021 and underwent a minimal access focused right superior parathyroidectomy for primary hyperparathyroidism in July 2022. Histology was consistent with a parathyroid adenoma weighing 0.69g. Repeat calcium in January 2023 was 2.34 mmol/L with PTH remaining mildly elevated at 7.1pmol/L. She was commenced on alendronate from January 2022 and switched to zoledronic acid in August 2022.
She re-presented one month after her parathyroidectomy in August 2022 due to acute on chronic pain and deformity of her left wrist having suffered a minor wrist injury 2 months prior. X-ray showed a lucent lesion in the distal meta-diaphysis of the radius that was not present on x-rays in 2019 or on follow up x-rays in 2020. MRI of her left wrist showed a multiloculated mixed cystic and solid lesion with areas of cortical thinning and destruction with surrounding periosteal oedema. Ultrasound-guided biopsy of the left distal radius in September 2022 showed cancellous bone composed almost entirely of tightly packed giant cells with osteoclast erosion of trabecular bone. The patient was given a presumptive diagnosis of brown tumour related to her recent surgically treated primary hyperparathyroidism.
She underwent left distal radius excision, fusion, and allograft of the tumour in February 2023 due to worsening left wrist swelling. Initial histology was again suggestive of a brown tumour. However, a GCTB was subsequently diagnosed, with stromal tumour cells showing strong nuclear positivity for histone H3.3 G34W on immunohistochemistry with breach of the bone cortex and tumour involving periosteum. The recommendation of the sarcoma MDM was for surgical revision and further imaging. Whole body turbo stir MRI in March 2023 showed generalised increased marrow trabecular signal with no discrete geographic lesion to suggest further destructive osseous lesions.
This is an unusual case that demonstrates the presumed coincidental diagnosis of primary hyperparathyroidism with a GCTB rather than the expected diagnosis of brown tumour. Brown tumours are well known to be associated with primary hyperparathyroidism, and solitary small brown tumours often regress post-parathyroidectomy.
GCTB represent 4-5% of primary bone tumours with a peak onset of 20-39 years and generally occur after skeletal maturity (2). There is a significantly higher incidence in Asian populations, with Paget’s disease thought to be a risk factor for their development (3). They commonly involve both the metaphysis and the epiphysis (4).
GCTB are locally aggressive but rarely metastasize. H3F3A gene mutation is detected in neoplastic stromal cells in as many as 95% of giant cell tumours (1). Immunohistochemistry shows the presence of mutant histone variant H3.3 G34W which is absent in brown tumours, and the expression of H3.3 G34V and H3.3 G34R have also been reported (1). H3.3G34W was found by Amary et al. in 2017 to be a sensitive and specific marker to differentiate GCTB from its mimics, particularly brown tumours. It is incorporated into chromatin and can be associated with epigenetic alteration on DNA methylation, chromatin accessibility and histone modification (5). RANK ligand is highly expressed by the stromal cells within GCTB which stimulates recruitment of osteoclastic cells from normal monocytic preosteoclast cells (6). The osteoclastic giant cells then absorb bone via a cathepsin K and matrix metalloproteinase 13 mediated process resulting in osteolysis (7).
Treatment ranges from intralesional options such as curettage to en bloc resection for extraosseous extension with or without reconstruction. The postoperative recurrence rates have been reported to be 10-65% (8). Denosumab use both in the neoadjuvant setting and where surgery is contraindicated can be helpful with a reduction in H3.3 G34W positive tumour cells and a decrease in osteoclastic giant cells accompanied by matrix and osteoid formation (9). Radiation therapy, arterial embolization and radiofrequency ablation should also be considered if surgery is contraindicated.
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