Inheritance of Osteosarcoma and Paget’s Disease of Bone

Case Presentations

A 33-year-old man with a 9-year history of Paget’s disease presented with a mass of the distal right femur with worsening pain, a recent 25-pound weight loss, and drenching night sweats. Several months before this, he had reported stiffness in his knees. The stiffness had been attributed to chronic osteomyelitis and leg length discrepancy and was treated with non-steroidal anti-inflammatory drugs and braces.

His past medical history was significant for multiple long bone fractures. At age 18 he fractured his femurs bilaterally in a motorcycle accident. At age 24 he suffered a left mid-femur fracture while jogging. Work-up at that time led to a diagnosis of Paget’s disease involving both femurs and proximal tibiae. Physical examination revealed tenderness, palpable fullness, and increased warmth through the distal right thigh.

Radiographs of the right knee and distal femur demonstrated severe bone deformity consistent with Paget’s disease and his prior healed fracture, but a soft tissue mass was identified posterior and medial to the distal femur emanating from the bone (Figure 1) . Chest radiographs identified two discrete pulmonary nodules. A bone scan revealed markedly increased flow to the right knee and right distal femur (Figure 2) .

A magnetic resonance imaging study demonstrated Paget’s disease involving the epiphysis and distal diametaphyseal region of the right femur. A large soft tissue mass was appreciated posteromedially adjacent to the thickened periosteum and cortex of the distal diametaphysis with distal extension (Figure 3) . The soft tissue mass was approximated to be 10 centimeters in greatest dimension.

The clinical and radiological data supported a presumptive diagnosis of Pagetoid osteosarcoma. An open biopsy of the right distal thigh mass showed a storiform, collagenized neoplasm with focal osteoid production. The cells were very pleomorphic, forming sheets in several foci. There were scattered tumor giant cells with a semicircular configuration of nuclei at the cell periphery. Mitotic figures were seen at a rate of approximately 60/10 high power field. The diagnosis of Grade 4 osteosarcoma, fibroblastic type, was made (Figure 4) .

The patient was treated with neoadjuvant chemotherapy, including high dose methotrexate, as per modified POG protocol 9450. A magnetic resonance imaging study performed following the neoadjuvant therapy showed a large, lobulated mass of the distal femur with soft tissue extension. The mass was similar to, but slightly larger than that described in previous studies. Additional lung nodules were identified at this time.

The patient underwent a right above-the-knee amputation, as the tumor involvement was too extensive to consider limb-sparing surgery. Examination of the amputation specimen showed Grade 4 osteosarcoma similar to that in the biopsy specimen. Gross examination of the specimen showed destruction of the metaphysis and tibial plateau. The tumor mass was thirteen by nine by eight centimeters and appeared to enter the knee joint space. Microscopic examination showed marginal necrotic bone and approximately 50% tumor necrosis identified. The resection margins were free from tumor, as confirmed by frozen section. Despite additional chemotherapy, including high-dose methotrexate, etoposide, ifosfamide, adriamycin, and platinum, with resection of multiple lung nodules, the patient succumbed to his disease almost 2 years following diagnosis.

The father of our patient presented at age 39 to Roswell Park Cancer Center in Buffalo, NY in early 1962 with abnormal x-ray findings of both distal femurs. A presumptive diagnosis of osteogenic sarcoma of both femurs was rendered. He underwent biopsies of both right and left femurs to confirm this presumptive diagnosis. Both biopsies illustrated Paget’s disease of bone. However, only the specimen from the right femur contained osteogenic sarcoma arising in the Paget’s disease. He underwent a right hip disarticulation. Nearly one year later, severe pain prompted x-rays of the chest, pelvis, and left leg. These all failed to demonstrate metastases or disease progression. Approximately six months later, the patient presented again with lesions of the left femur and tibia including a pathological fracture through the upper left tibia. An open biopsy performed at this time showed osteogenic sarcoma of the left leg. X-rays of the chest demonstrated two discreet pulmonary nodules, believed to be metastatic involvement. The patient was treated with BCNU (bis-chloronitrosourea, carmustine) for 3 days but suffered severe toxicity. No further chemotherapy or surgery was initiated. The patient succumbed to his osteosarcoma 3 months later, less than 2 years after his initial diagnosis.

Materials and Methods

Results

Results from the 18q microsatellite markergenotyping are shown in Figures 5 and 6 . Unfortunately no material was available from the affected father (I:1), though his genotype could be partially reconstructed from his offspring. Loss of heterozygosity involving the maternally inherited alleles was detected in the tumor (II:5) as compared to the blood (II:4). Markers in 18q21.2 (D18S858), 18q22.1(D18S68, D18S1113, D18S878) were detected in reduced amounts indicating a chromosomal deletion. The reduced amounts rather than complete absence of the maternal allele indicated that the tumor sample included non-tumor tissue. The maternally inherited MBP microsatellite allele in 18q23 did not appear to be deleted in the tumor. Thus the distal breakpoint appears to lie between D18S878 and MBP. The proximal breakpoint was not defined but appears to lie proximal to D18S858. All other markers were uninformative.

This result is consistent with the paternal transmission of a mutation in a putative tumor suppressor gene that is uncovered by an acquired “second hit” deletion including 18q22.1 in the tumor. The carrier status of this putative tumor suppressor mutation in the three unaffected siblings is uncertain given the lack of an exact location of the tumor suppressor and the lack of a paternal sample to genotype.

Discussion

Worsening pain, pain resistant to analgesics, or changes in the pain pattern often signals the development of osteosarcoma in Paget’s disease. 26^, 27 Swelling, fracture, weight loss, night sweats, and neurological complaints may accompany these symptoms. 2^, 28 The typical presentation of an affected patient with sarcomatous transformation is a 65-to-70 year-old man with a 15-to-25 year history of polyostotic Paget’s disease. 2^, 27^, 28^, 29 The sarcoma itself is usually high grade with a poor prognosis. 29 Some researchers have attributed the low survival in Pagetoid osteosarcoma to effects of advanced age: a weakened immune system, a decreased ability to battle the disease, and decreased tolerance of treatment, 27 for example. Other factors, such as environmental exposure, may also prove significant though proof is lacking. However, both patients described here were significantly younger than those typically affected by these disease processes, though they did exhibit some of the classic symptoms. The x-ray findings in our patient clearly show involvement by the sclerotic phase of Paget’s disease, suggesting a long disease course.

Both of these patients had involvement of the distal femur, a common site of involvement for both the diseases. 2^, 27^, 30^, 31 One previous report of a father and son affected in identical locations describes a father, affected at age 78, and son, affected at age 60, with Pagetoid osteosarcoma. Both men were affected at the proximal tibia, had long histories of Paget’s disease leading up to the sarcomatous transformation, and died of their disease within months of diagnosis with evidence of pulmonary metastases. 18 Previous to that report, Paget’s disease was considered to be transmitted as an incompletely dominant X-linked gene. That case was the first to give credence to male-to-male transmission, initiating research to explore the possibility of involvement of an autosomal gene. Since this time, evidence has pointed to several genes linked to Paget’s disease, some as yet unidentified. Linkage analysis studies first uncovered an apparent link to the HLA locus on chromosome 6, now termed PDB1. 11

Further study provided evidence of linkage between Paget’s disease and a susceptibility locus on chromosome 18q21–22. This locus harbors the gene identified in a family afflicted with familial expansile osteolysis, a rare bone disorder with features very similar to Paget’s disease. 6^, 13 A subsequent study has also identified a putative tumor suppressor gene on chromosome 18q. In that study, all tumor samples examined from individuals affected with Pagetoid osteosarcoma showed some loss of heterozygosity in the 18q21–22 region studied. A lower percentage of tumor samples from sporadic osteosarcoma, those not superimposed on Paget’s disease, also showed loss of heterozygosity in this same region. 4 This is in contrast to the more conventional high-grade osteosarcomas occurring in children affected with retinoblastoma, as part of the Li-Fraumeni syndrome, or in so-called cancer families. 32^, 33^, 34 Another study used seven polymorphic loci in this region of chromosome 18q21–22 in eight genetically diverse families affected by Paget’s disease only. Five of eight showed linkage to the region, while two showed no linkage and the last family was inconclusive. Interestingly, three of the families were of Spanish decent, yet one showed linkage to this region. 5

Our genetic analysis does support the idea of a susceptibility region on chromosome 18 in the region described previously. 4^, 5^, 6 Work to definitively determine the associated gene would potentially be helpful in further understanding the disease etiology. The gene encoding the receptor activator of nuclear factor-κ B (RANK, TNFRSF11A) lies within the critical region of 18q that has been deleted. The RANK gene represents a strong candidate gene since it has been found to be mutated in familial expansile osteolysis. 35 Although thus far the RANK gene has not been found to be mutated in Paget’s disease of bone, Wuyts did find a statistical association between a RANK polymorphism and Paget’s disease of bone, indicating that it may represent a susceptibility factor 36^, 37 Sequencing of this gene in the presented family, as well as examination of other regions, including the PDB1 locus may uncover more information.

Other siblings within this family may have inherited the same alleles as our patient. However, these siblings, ranging in age from 39 to 44, do not show any signs of Paget’s disease or Pagetoid osteosarcoma to this point. Although they are younger than the typical age for diagnosis with either disease, they are both older than their family members were at initial presentation. Why only one offspring was affected by severe Paget’s disease and Pagetoid osteosarcoma is not easily explained. The similarity of his disease to that of his father is curious. Perhaps elucidation of the gene involved will clarify the mechanism. This may be the key to improving the dismal prognosis associated with this disease.