Moderators: Dr. K. Krishnan Unni and Dr. Franco Bertoni
Case 5 -
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.
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
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 . 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
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 . The oncogenic cause of osteomalacia may be
unrecognized because the tumors are frequently small , asymptomatic, or appear several years after the
recognition of osteomalacia .
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  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.  suggestied the term
"sclerosing hemangioma". Other authors have used such descriptive terms as "benign angiofibroma" ,
"primitive mesenchymal tumor" . The diversity of
these diagnostic terms underscored the morphologic complexity of the tumors and the difficulty in
developing a single universally acceptable term . 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
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. . 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.  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
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
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 . FGF-23 is
hightly expressed in oncogenic osteomalacia tumors
but only low levels in normal tissue .
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 .
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