INTRODUCTION

Paget’s disease of bone (PDB) is the second most common disease of bone metabolism after osteoporosis. It is characterized by localized areas of accelerated, disorganized, and excessive bone production and turnover. Almost any bone can be affected, but there is a predilection for the pelvis, spine, femur, tibia, and skull^[1]. Paget’s disease is more common in males and in certain ethnic groups. Whites are the most commonly affected and it is estimated that the disease occurs in approximately 1% of people over 55 years of age in European countries.

Neoplastic transformation of the lesions is a rare complication of PDB, which affects about 0.3% of patients. The majority of these malignancies are sarcomas, with osteosarcoma by far the most common^[2].

Documented cases of primary lymphoma of bone (PLB) associated with preexisting Paget’s disease in that same bone, has been described on rare occasions^[3]. Primary hyperparathyroidism (PHPT) is rarely found in patients with PDB, although it has been suggested that these patients may have an increased risk of secondary and tertiary hyperparathyroidism^[4]. Additionally, coexistence of PHPT and non-Hodgkin lymphoma (NHL) has also been described, although whether is incidental or related has not been elucidated^[5].

We present a case of MHL arising in pagetoid bone in a patient who was subsequently diagnosed with PHPT.

CASE DESCRIPTION

A 56-year-old white man who had experienced 3 months of progressive left pretibial pain following a blow to the left leg was referred to our clinic. He had a history of congenital ankylosis of the hands and bilateral deafness. The physical examination was remarkable only for a small painful lump in the left pretibial area. Neither lymphadenopathy nor hepatosplenomegaly was seen. Routine laboratory data were normal. Total skeleton bone scintigram, computed tomography (CT) scan, and magnetic resonance imaging (MRI) were subsequently obtained (Fig. 1 and 2). These images revealed isolated skeletal abnormalities in the left leg. A CT-guided biopsy was performed, and histopathological findings were compatible with monostotic PDB (Fig. 3). He was treated with zoledronate with remission of pain. Three years later, recurrent pain began in the same area. Follow-up plain radiographs, CT and MRI, showed that the lytic and soft tissue component had progressed (Fig. 4), so a new CT-guided bone biopsy was performed, revealing a large cell lymphoma of bone with centroblastic morphology (Fig. 5). He was treated with rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, prednisone (R-CHOP) and a new dose of zoledronate, with a good response. Two years later, hypercalcemia (albumin-corrected calcium: 10.7 mg/dl, ionized calcium 1.48 mM), hypophosphatemia (1.9 mg/dl) and hypercalciuria (335.5 mg/24 hours) was detected. PTH levels were raised (246 pg/ml). Cancer antigens were negative, while other laboratory tests were normal. Further investigation with parathyroid scan was compatible with a right lower parathyroid adenoma. After surgical removal of the adenoma, biopsy confirmed the diagnosis. Presently, 1 year later, the patient remains relapse free, and he is asymptomatic.

DISCUSSION

The malignant potential of pagetoid bone is well known. Malignant neoplasms associated with PDB are most often metastases, and, rarely, primary malignant transformations. Sarcomatous degeneration is the most common of these, although it is actually a rare complication of PDB which affects about 0.3% of patients^[1]. Primary lymphoma of the bone arises from the medullary cavity and presents as a focal, solitary lesion, which is extremely rare and only represents around 3% of primary bone malignancies and 1% of lymphoma^[6]. Therefore, it is not surprising that lymphomatous complication of PDB has been rarely observed. Although other cases of bone lymphoma associated with PDB have been described, they were diagnosed more than 40 years ago, so the classification of lymphoma would be difficult to establish with current diagnostic criteria^[6]. Given the low frequency of this association, it is difficult to determine in this case whether there was actually lymphomatous transformation of PDB or fortuitous coexistence of these two diseases.

Overproduction of PTH is reported in 12-18% of PDB^[4]. Whereas the pathophysiological relationship between PDB and secondary HPT is well established^[7,8], the aetiology of the association of PDB and primary HPT is a matter of debate. In fact, adenoma or hyperplasia of the parathyroid glands is rarely found in patients with PBD. The estimated prevalence is 2.2-6% based on large PBD cohorts, with more women being affected than men, a prevalence similar to or slightly higher than that in the general population, between 1 and 3% in men and women over 60 years old, suggesting that there is no etiologic link between the two disorders. However, the fact that SQSTM1 gene, which is involved in the pathogenesis of PBD, and multiple endocrine neoplasia type 1 (MEN 1), share the same signalling pathway through nuclear factor kappa beta (NF-kB), raises the possibility that there could be a connection between PBD and PHPT^[7,8]. Besides, several studies have shown a link between hyperparathyroidism and an increased risk of malignancy, including lymphoma^[5]. Whether the coexistence of PHPT associated with lymphoma is incidental or related has not been elucidated. Studies have shown that CDKN1B mutations, a gene that encodes P27 protein, a member of the CDK inhibitor (CDKI) family that regulates cell cycle progression, could play a role as susceptibility genes for sporadic PHPT lymphoma, and other tumours^[9].

CONCLUSION

The association of NHL and PHPT with PDB are rare. Nevertheless, it is advisable to be vigilant, and to investigate bone metabolism parameters in patients with PDB, as a means of monitoring the activity of the disease, the response to treatment and identification of the other underlying bone pathologies. It is unknown if there is any mechanism that can link these three diseases.