Inheritance of osteosarcoma and Paget's disease of bone: a familial loss of heterozygosity study

Abstract

Pagetoid osteosarcoma is a complication of Paget's disease of bone. Sarcomatous transformation is most often seen in severe, long-standing Paget's disease. Familial clustering of Paget's disease has been described with apparent autosomal dominant inheritance with high penetrance by the sixth decade. Although definitive proof of the specific gene involved remains elusive, some researchers have shown loss of heterozygosity in a region of chromosome 18q in a relatively high percentage of studied patients affected with either Paget's disease alone, in Pagetoid osteosarcoma, and in uncomplicated osteosarcoma. Our patient was diagnosed with Pagetoid osteosarcoma and had a first-degree relative with history of the same. We hypothesized that our patient's tumor samples might contain a similar genetic abnormality. Our analysis of several polymorphic markers from the chromosome 18q21-22 region showed loss of maternally inherited alleles throughout the region. This finding is similar to those described previously and provides further evidence of a susceptibility region relating to this disease. This report describes a father and son, their young ages at diagnosis of Pagetoid sarcoma, the identical sites of disease involvement, and a loss of heterozygosity study illustrating the inheritance of the presumed defective gene.

Figure 1.

Anteroposterior radiograph of the right distal femur shows severe deformity due both to the underlying Paget’s disease and a healed distal femoral fracture. A soft tissue mass is shown extending posteromedially (arrows). Pagetoid involvement of the adjoining proximal tibia is also seen.

Figure 2.

Total skeleton bone scan shows increased uptake in the medial and lateral condyles and distal medial cortex of the right femur, with a negative image created by the tumor mass (arrow).

Figure 3.

Magnetic resonance imaging coronal T1 weighted spin echo (A) and coronal T2 weighted fast spin echo (B) show a large lobulated tumor mass arising from the epiphysis and distal diametaphysis. The mass (arrows) shows low signal on T1-weighted images and hyperintensity on T2-weighted images.

Figure 4.

Histological sections of the tumor mass (A, B) demonstrate the hypercellular storiform tumor mass. Mitotic figures are extensive. Focal scant osteoid production is identified in A (arrows) diagnostic of osteosarcoma. Histological sections of bone away from the sarcoma within the resected distal femoral specimen (C) illustrate haphazardly organized, thickened trabeculae and irregular cement lines consistent with bone involved by Paget’s disease after neoadjuvant chemotherapy. A: Trichrome stain, ×20; B: Hematoxylin and eosin, ×40; C: Hematoxylin and eosin, ×20).

Figure 5.

Pedigree microsatellite genotype results. The index case is represented by post-surgical non-tumor specimen (II:4) and post-surgical tumor specimen (II:5).

Figure 6.

A: D18S858 PCR product from blood (lane 1) and from tumor of the index case (lane 2). Run on an 8% polyacrylamide gel for 11,000- volt hours. Note that allele 1 (•) of the tumor is present in reduced amounts compared to allele 1 in blood (x). B: In contrast, in lane 3, MBP PCR product from blood, and lane 4, from tumor of the index case show no evidence of loss of heterozygosity.