Introduction

Brown tumour (BT) is a benign bony lesion caused by rapid osteoclastic turnover of bone which is localised, resulting from direct effects of increased parathyroid hormone (PTH) seen in primary hyperparathyroidism (PHPTH) or secondary/ tertiary hyperparathyroidism (SHPTH/ THPTH). BT have been reported to occur in 2-3% patients of HPTH, hence rarely seen in clinical practice [1]. Clinically, BT can present with pain in the bones renal stones abdominal groans along with psychiatric manifestations [2]. About 70% to 80% of cases present asymptomatically and get incidentally picked up while screening of calcium, phosphate levels during other investigations In contrast, advancements in biochemical screening and increased clinical awareness have enabled the early detection of PHPT, often in asymptomatic individuals. Nonetheless, normocalcemic hyperparathyroidism may represent an incipient form of the disease [3]. The diagnosis of BT requires a high index of suspicion as it is based on a battery of tests from medical history, clinical examination, laboratory results to radiological imaging, where surgical biopsy and histopathological evaluation are definitive for diagnosis [4]. We present here, two cases with the rare and first presentation of pathological fractures and with histopathological diagnosis of BT being crucial for the final work up leading towards the diagnosis of PHPTH due to parathyroid adenoma in both the cases.

Case Presentation

Case 1

A 43 year old male presented with a left femur fracture, with history of right tibia fracture four months back. He complained of generalized fatigue and bony pains. Body Bone scan was advised which revealed multifocal involvement and suggested the diagnosis of Metabolic bone disease possibly Multifocal low grade infective/ inflammatory pathology. Few excised bony tissue bits after open reduction and internal fixation with intramedullary femur nailing, showed multiple yellow brown soft to firm tissue pieces altogether measuring 2x2x1cm were sent for histopathological examination. Microscopic examination revealed groups and clusters of multinucleated osteoclastic giant cells along with cells having oval to spindle bland nuclei with indistinct cells borders and eosinophilic cytoplasm. Viable and necrotic bony trabeculae with intervening areas showing trilineage haematopoiesis seen [Figure 1]. Thin and thick walled blood vessels and hemosiderin deposition also seen along with large areas of haemorrhage.

Figure 1: A - Low power view photomicrograph showing giant cell clusters with surrounding prominent foci of haemorrhage. (H&E, 10X). B - High power view photomicrograph showing sheets of mononuclear cells admixed with multinucleated osteoclastic giant cells. Haematoxylin and eosin stain (H&E, 40X)

Case 2

A 36 year old male presented with pain and deformity at the site of five month old fracture site, left humerus. X ray revealed decreased bone density. Multiple grey brown soft to firm tissue bits from intramedullary bone of fracture site, altogether measuring 1.5x1.5x0.2cm was received for histopathological examination, foci of fibroblastic proliferation along with foamy histiocytes, occasional multinucleated giant cells and scattered hemosiderin laden macrophages were seen along with enmeshed bony trabeculae and unremarkable hematopoietic elements [Figure 2].

Figure 2: A - Pathological fracture of the left humerus in Case 2. B- Low power view photomicrograph intervening areas of trabeculae showing trilineage haematopoiesis and areas of haemorrhage. Haematoxylin and eosin stain (H & E, 10X). C - High power view photomicrograph showing groups and clusters of multinucleated osteoclastic giant cells (arrow) along with cells having oval to spindle bland nuclei with indistinct cells borders and eosinophilic cytoplasm. Histiocytes and hemosiderin laden macrophages also seen. Haematoxylin and eosin stain (H & E, 40X)

Histopathological diagnosis in Case 1 was BT and further work up was advised. On work up the patient had markedly raised PTH > 2500pg/mL and phosphorus levels were low at 1.9mg/dL and. A clinical diagnosis of hyperparathyroidism was made, thereafter a Sestamibi scan was also performed and presence of left inferior parathyroid adenoma was identified. Similarly, histopathological features in Case 2 was suggestive of BT and laboratory and radiological correlation was advised. Patient was advised Sestamibi scan for parathyroid adenoma localization based on the histopathological diagnosis of BT and on scan inferior parathyroid region shows an enlarged homogenous hypoechoic lobulated mass 6 x 2.1 x 1.4 cm with peripheral vascularity, suggestive of Right Inferior Parathyroid Adenoma. Ultrasonography was also suggestive of right parathyroid adenoma. Patient’s calcium level was 13.4mg/dL with elevated PTH >2500pg/mL. Both patients recovered after orthopaedic procedures. They both underwent parathyroidectomy. Recovery after surgery which was uneventful with normal values of serum PTH and calcium levels.

Discussion

Von Recklinghausen termed osteitis fibrosa cystica back in 1891, as a classical bone disease usually seen in severe PHPTH. The popular term, “brown tumour” was given by Jaffe owing to reddish brown colour of the lesion due to the high vascularity and hemosiderin pigment. Increased bone resorption on both subperiosteal and endosteal surfaces due to high circulating levels of PTH, led to the misnomer for this entity, and “osteoclastoma” is often used. These lesions are non-neoplastic, resulting from a reparative process histologically [4]. In this report, we have reviewed literature where BT was the first presentation of PHPTH along with comparison of age, sex and site of presentation [Table 1].

BT are seen commonly in females and more common in people in their 4^th and 5^th decade [5]. However, both our cases and the cases reported by Aldosari et al and Ruibin et al were seen in young and middle aged male patients [1,6]. Frequently involved sites are craniofacial bones then the long bones and ribs [6]. In our cases, as well as study by Haouzi et al and Saini et al., lesions were localised in the long bones [2,7]. BT with their rare incidence shows late manifestation in PHPTH. Contrary to this in both our cases these lesions were caught on early. BT has a higher incidence of 13% in secondary HPTH. Main causes of PHPTH are parathyroid adenoma, accounting for 85%, parathyroid hyperplasia, accounting for 10–15%, and carcinoma, accounting for 1–5% [4]. The clinical presentation are variable ranging from muscle weakness fatigue stones recurrently and fractures [1]. PHPTH leads to high concentration of calcium and phosphorus which causes urinary stones caught on abdominal ultrasound or on a CT scan easily and early [8]. Both our cases had a history of repeated fractures

Radiologically BT are often misdiagnosed for metastases or even primary cancer when they present as diffuse osteolytic lesions large lytic lesions [9 OLATOKE]. However, histopathological evaluation is the gold standard and IHC correlation is always preferred. Microscopically BT represent localized proliferation of fibrous tissue and giant cells, which can replace bone and may produce osseous expansion. Differential diagnoses can be many like giant cell lesions such as solid aneurysmal bone cyst (solid ABC), GCTB and giant cell reparative granuloma (GCRG) [6]. Solid ABC on histopathology shows large cystic spaces and fibrous septa showing scattered multinucleated giant cells along with rimming of osteoblasts around the reactive woven bone. GCTB has often been confused with BT, where the osteoclastic giant cells are more evenly spaced, the stromal cells are plumper and not so spindly as in BT, and osteoblastic activity is less conspicuous. The distinction with GCRG may be impossible on morphologic grounds because both lesions have a predilection for the jaw and their microscopic appearances are essentially the same; therefore the distinction is based on laboratory findings and history [6]. Immunohistochemistry (IHC) can also be of use here. Negativity for IHC markers TRAP and cathepsin K in the multinucleated giant cells of BT was studied and suggested by Toriu et al in cases of diagnostic dilemmas [3]. Complete surgical resection in hyperfunctioning parathyroid tissue is crucial for curative treatment of PHPTH [9]. It is important to identify BT from other benign bone lesions, at an earlier stage in order to reduce the morbidity and to prevent over diagnosis/ aggressive treatment of metastasis/ primary bony malignancies.

Conclusion

These two case emphasise the need of inclusion of BT in the differential diagnosis of pathological fractures or multifocal osteolytic bone lesions, to not only avoid unnecessary surgical interventions but for more extensive work up with serum phosphate calcium and PTH levels, along with imaging. As seen in both our cases, BT can be masked by fractures at the time of presentation. Thus, evaluation of debrided tissue of these fracture sites cannot be emphasised enough as histopathology is most definitive for the diagnosis. The histopathological differentials of solid ABC, GCBT and GCRG though seemingly similar on morphology have their distinct nuanced differences which need to be evaluated thoroughly on microscopy.

References

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