Case 5 -

Oncogenic Osteomalacia Yong-Koo Park, MD Kyung Hee University Seoul , Korea

Oncogenic osteomalacia, is an acquired, paraneoplastic syndrome of renal phosphate-wasting that resembles genetic forms of hypophosphatemic rickets. Case History: The patient is a b47-year-old man suffering from low back pain and lower extremity weakness for 2 years. Before visiting this hospital, he visited another hospital and took a bone scan and it revealed multiple hot uptakes on the both ribs, hip, tibia and right femur neck. Simple x-ray of the right femur showed osteolytic lucent lesion at the diaphysis and also showed cortical thinning. His blood chemistry revealed slightly lower serum calcium (10.6 mg/dl) and phosphorus (1.2 mg/dl) and high alkaline phosphatase activity (303U/L). Curettage was done on the right femoral diaphyseal lesion. Case 5 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer The first case of a phosphatemic connective tissue tumor was suggested in 1947 by McCance in a report of "degenerate osteoid tissue" occurring in the distal femur of a 17-year-old girl [ 1]. And later on, in 1959 Prader et al. described the underlying cause of this unique syndrome in an 11-year-old girl with a giant cell reparative granuloma of the rib [2]. Patients with oncogenic of tumorous osteomalacia have mesenchymal tumors that somehow lead to hypophosphatemia, normocalcemia, renal phosphate leak, increased alkaline phosphatase, and osteomalacia. The definition requires that there be no family history or rickets, heavy metal poisoning, or conditions giving rise to Fanconi's syndrome [3, 4, 5, 6, 7, 8, 9]. Oncogenic osteomalacia is an unusual and interesting syndrome usually manifested in early adult life. The clinical course is typically protracted. In some cases, the initial clinical presentation is mistaken for rheumatoid arthritis, muscular dystrophy, or primary neurologic disorder. In some instances, a pathologic fracture is the first sign [10]. The oncogenic cause of osteomalacia may be unrecognized because the tumors are frequently small [8], asymptomatic, or appear several years after the recognition of osteomalacia [11]. Up to now there are about 136 cases of oncogenic osteomalacia published in English literature. These cases can be divided into 5 categories, such as soft tissue tumors, bone tumors, epithelial tumors, oral lesions and others. Soft tissue tumor is the most common cause. Among the soft tissue tumors, phosphaturic mesenchymal tumor is the most common cause of oncogenic osteomalacia. It is apparent that phosphaturic mesenchymal tumors represent a heterogeneous group. The terminology for these primitive tumors is still a matter of controversy [12] suggested the term "ossifying mesenchymal tumor associated with osteomalacia". However, not all tumors contain ossified areas, and it is sometimes difficult to differentiate reactive bone formation from true tumoral bone. Salassa et al. [13] suggestied the term "sclerosing hemangioma". Other authors have used such descriptive terms as "benign angiofibroma" [14], "hemangiopericytoma" [15], "chondrosarcoma" [16], "primitive mesenchymal tumor" [7]. The diversity of these diagnostic terms underscored the morphologic complexity of the tumors and the difficulty in developing a single universally acceptable term [8]. In 1987, Weidner and Santa Cruz suggested that until the specific cell type or phosphaturic substance is characterized, it is best to use a descriptive phrase to label these tumors. The diagnostic phrase they preferred for the tumors occurring in soft tissue was "phosphaturic mesenchymal tumor(mixed connective tissue variant)." For those occurring in bone resembling osteoblastomas, they favored the phrase "phosphaturic mesenchymal tumor (osteoblastoma-like variant)." The most characteristic histologic findings are the presence of capillary-sized, slit like hemangiopericytomatous vascular proliferation, matrix calcification, and giant cells. A hemangiopericytomatous slit-like, capillary vascular proliferative pattern is identified in 50% of cases. A hemangiopericytomatous vascular pattern is seen in various bone sarcomas, including osteosarcoma and mesenchymal chondrosarcoma. However, it is not common in any tumor except mesenchymal chondrosarcoma. The largest series reported by Park et al. [17]. among the 17 bone tumors, 7 showed dystrophic matrix calcification, and in 5 there was diffuse-to-focal fine lattice-like calcification. The rest of the lesions showed punctate or grouped calcification. The lace-like matrix calcification is very characteristic and often suggests the possibility of hypophosphatemic osteomalacia. However, calcification is not always seen and not all the tumors with calcification occur in patients with the syndrome. Calcification is common in bone neoplasmas such as chodroblastoma and osteosarcoma. However, the peculiar patchy matrix dystrophic calcification seen in seven tumors in Park et al. series is quite distinctive. This calcification is unlike that seen in the matrix of osteosarcoma. The distincitive calcification and the presence of hemangiopericytomatous slit-like capillary vascular proliferation in some of the other neoplasm suggest an association with osteomalacia. Of the lesions, 60% contains multinucleated giant cells. Giant cells are irregulary distributed in all but one lesion, and the number of giant cells was highly variable. Weidner et al. [7] concluded from their election microscopic study that the giant cells were osteoclast-like in appearance. Recent study has suggested that the osteoclast-like multinucleated giant cells are not critical in the pathogenesis of oncogenic osteomalacia [18]. Through the tumor cultures or tumor extracts inhibit phosphate transport, slow growth of cultured tumor cells and the frequent loss of phosphate-inhibitory activity in culture hampered the identification of the phosphaturic substance produced by these tumor cells. Several studies have identified varies candicate genes for the phosphaturic substance produced by these tumors [19, 20, 21]. Including among these genes is fibroblast growth factor-23 (FGF-23), a novel FGF, which was contemporaneously idenfitied by positional cloning as the defective gene in autosomal dominant hypophosphatemic rickets [22]. FGF-23 is hightly expressed in oncogenic osteomalacia tumors [19, 21, 23] but only low levels in normal tissue [22]. Usually, a dramatic reversal to a normal bone metabolism occurs after the benign tumor is excised. It is well documented that incomplete removal of the primary lesions or recurrence is indicated by reappearance of hypophosphatemia and bone pain [11]. References McCance RA: Osteomalacia with Looser's nodes(Milk-man's syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years. Q J Med 16: 33-46, 1947. Prader A, lllig R, Uehlinger E, Stalder G: Rachitis infolge Knochentumors. Helv Paediatr Acta 14: 554-565, 1959. Thompson ER, Baylink DJ, Wergedal JE: Increases in number and size of osteoclasts in reponse to calcium or phosphorus deficiency in the rat. Endocrinology 97: 283-289, 1975. Drezner MK, Feinglos MN : Osteomalacia due to 1 ⍺ 25-dihydroxycholecalciferol deficiency: association with a giant cell tumor of bone. J Clin Invest 60:1046-1053, 1977. 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