Phosphaturic Mesenchymal Tumor-Inducing Oncogenic Osteomalacia Yong-Koo Park Kyung Hee University Hospital Seoul, South Korea

Clinical History A 56-year-old woman presented with a 3-year history of diffuse, increasing bone pain at multiple locations. She also suffered from generalized fatigue and difficulty walking. There was a more recent history of protruding mass on her right foot sole. Laboratory data at the admission showed the following: serum phosphorus 1.1 mg/dl (normal range 2.5-4.5 mg/dl), calcium 9 mg/dl (normal range 8.2-10.8 mg/dl) and alkaline phosphatase 625 IU/l (normal range 96-254 IU/l). Urinary excretion of phosphorus was 392 mg/day and tubular reabsorption of phosphorus was markedly decreased at 59.6% (normal range 92-95%). Pelvic X-ray revealed a marked decrease in bone densities and multiple pseudogractures. Plain radiograph of the foot showed marked osteopenia and an ill-defined lobulated mass with pressure erosion of the second and third metatarsal bones. A bone biopsy was performed. Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Figure 1 Heavy calcification and granulation tissue-like blood vessel proliferation are noted. Figure 2 Higher magnification shows prominent capillary endothelial cells and loose myxoid stroma and some scattered histiocyes. Figure 3 In the area, there is cystic change and some necrosis with calcification. Figure 4 Higher magnification shows the cyst wall with calcification. Figure 5 In some areas, the cyst wall is composed of some histiocytes and calcified materials. Figure 6 In solid parts, cellular areas show thick blood vessel calcification and some histiocytes. Figure 7 Higher magnification shows osteoclast-like giant cells and some plasma cells. Figure 8 There is also noted prominent hemangiopericytomatous blood vessel proliferation and some giant cell calcification. Introduction: Osteomalacia (Greek: osteon, bone and malakia, softness) is a defect in the mineralization of the preosseous matrix of mature lamellar bone that leads to an accumulation of nonmineralized or poorly mineralized osteoid over the surfaces of both compact cortical and spongy trabecular bones. Patients with oncogenic or tumor-induced osteomalacia have mesenchymal tumors that somehow lead to hypophosphatemia, normocalcemia, renal phosphate leak, and increased alkaline phosphatase. The cause of oncogenic osteomalacia may be unrecognized because the tumors are frequently small, asymptomatic, or appear several years after the recognition of osteomalacia. Histologically, the lesion shows variable microscopic pictures which do not fit the patterns of any particular disease entities. Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: Histologically, osteomalacia lesions show large areas of necrosis with dystrophic calcification. Also noted are numerous blood vessel proliferations forming hemangiopericytomatous patterns. In the affected area, there is cystic change simulating a secondary aneurysmal bone cyst. In some areas, osteoclastic giant cells and histiocytes are noted. Immunohistochemically, fibroblast growth factor (FGF23) is positive among the mesenchymal cells present in the septae. Dentin matrix protein 1 (DMP1) is also positive in the cytoplasm of the histiocytes and in some giant cells. Matrix extracellular phosphoglycoprotein (MEPE) is also positive in the cytoplasm of the mesenchymal cells. Differential Diagnoses: Due to the large extensive destructive lesion of the metatarsal bone, osteosarcoma is listed as one of the differential diagnoses. However, histologically, there is no evidence to support malignant-looking tumor cells. Chondromyxoid fibroma is also considered as a differential diagnosis. There is a large area of fuzzy calcification leading to a vague lobular appearance. There is, however, no definite evidence of lobular appearance consisting of a central hypocellular lesion and hypercellular lesion at the periphery. Final Diagnosis: Phosphaturic mesenchymal tumor-inducing oncogenic osteomalacia Case Discussion: This is a case of a bone tumor that occurred on the metatarsal bone, which is a very rare site for a bone tumor. A biopsy was performed due to suspicion of malignancy from radiologic studies. Upon biopsy, the histologic features did not correlate with any other typical bone tumors. In conjunction with clinical laboratory findings, such as hypophosphatemia and increased renal phosphate leak, it was determined that this is a case of typical tumor- induced osteomalacia, or oncogenic osteomalacia. Review of the Literature/Treatment Options: Osteomalacia (literally "soft bone") is due to poor mineralization of the osteoid. As a result, unmineralized osteoid accumulates on trabecular bone and cortical bone surfaces. The etiology is remarkably diverse, ranging from congenital cases such as inborn errors of metabolism to chronic renal failure. An unusual and rare presentation of osteomalacia results from the paracrine effect of any type of epithelial or mesenchymal tumor and timorous conditions. In this syndrome, known as oncogenic or tumor- induced osteomalacia (OO), a tumor synthesizes and secretes the phosphate-leaking substance, phosphatonin, which acts on the kidneys through circulation. In 1947, McCance described the first case of oncogenic osteomalacia; however, he did not notice the patient's femoral lesion as the cause of osteomalacia. In 1959, Prader et al. first recognized the etiology of osteomalacia in their report of a giant cell reparative granuloma of the rib of an 11-year-old girl. Since then more than 100 cases of OO have been reported in the literature, most of which are case reports or a study of very small numbers. The biochemical features characterizing this syndrome show hypophosphatemia and an abnormally low renal tubular reabsorption of phosphorus, indicative of renal phosphate wasting. Usually, after the successful removal of the tumor, the level returns to normal. In OO, serum 25(OH)D is normal and serum 1,25(OH)2D is overtly low or inappropriately normal relative to the low phosphates serum level. Radiographic abnormalities include generalized osteopenia, pseudofractures, and coarsened trabeculae, as well as widened growth plates in children. The tumors presented in OO are of mesenchymal origin in the large majority of patients. However, some patients with epithelial tumors also have OO, such as breast carcinoma, prostate carcinoma, oat cell tumor, small cell carcinoma, multiple myeloma, and chronic lymphocytic leukemia. The mesenchymal tumors inducing OO have been variably described as sclerosing angioma, benign angiofibroma, hemangiopericytoma, chondrosarcoma, primitive neuroectodermal tumor, soft parts chondroma-like tumor, and giant cell tumor of the bone. The diversity of these syndromes is indicative of the morphologic complexity of these tumors. However, in 1987, Weidener and Cruz established that the histologically polymporphous mesenchymal tumors can be subdivided into four distinct morphologic patterns: (i) primitive-appearing, mixed connective tissue tumors; (ii) ostoeblastoma-like tumors; (iii) nonossifying fibroma-like tumors; and (iv) ossifying fibroma-like tumors. The most common of these is the mixed connective tissue variant, which behaves in a benign fashion and is characterized by variable numbers of primitive-appearing stromal cells growing in poorly defined sheets and punctuated by clusters of osteoclast-like giant cells, microcysts, prominent hemangiopericytic vascular patterns, a cartilage- like matrix, and metaplastic bone. The pathophysiologic basis underlying OO remains unknown. Most researchers agree that tumor production of a humoral substance, phosphatonin, that may affect multiple functions of the proximal renal tubule, particularly phosphate reabsorption (resulting in hypophosphatemia), is the probable pathogenesis of OO. One of the known phosphatonins is fibroblast growth factor 23 (FGF23). The mesenchymal tumors causing OO express and secrete FGF23 and other phosphaturic proteins. The FGF23 gene, which resides on human chromosome 12p13 (mouse chromosome 6), is comprised of three coding exons and contains an open reading frame of 251 residues. The tissue with the highest FGF23 expression is bone, and FGF23 mRNA is observed in osteoblasts, osteocytes, flattened bone lining cells, and osteoprogenitor cells. FGF23 reduces renal Pi reabsorption but has opposite effects on 1,25(OH)2D. The two primary transport proteins responsible for Pi reabsorption in the kidney are the type II sodium-phosphate co-transporters, NPT2a and NPT2c, expressed in the apical membrane of the proximal tubule. FGF23 delivery leads to renal Pi wasting through the downregulations of both Npt2a and Npt2c. Circulating levels of FGF23 are elevated in most patients with OO. After surgical resection, FGF23 levels normalize. Other secreted proteins such as MEPE (matrix extracellular phosphoglycoprotein), FGF7, sFRP4 (secreted frizzled related protein 4), and DMP1 (dentin matrix protein 1) are highly expressed in mixed connective tissue variants of phosphaturic mesenchymal tumor. MEPE is also called osteoblast/osteocyte factor 45, as it is mainly expressed in osteoblasts and osteocytes and was first identified in a cDNA library of OO. The MEPE gene encodes a 525-amino acid extracellular matrix protein. MEPE shares a sequence homology with the small integrin binding ligand, N-linked glycoprotein (SIBLING) family protein such as bone sialoprotein, dentin sailophosphoprotein, osteopontin, and the dentin matrix protein; all of which are clustered on chromosome 4q21 in humans and chromosome 5q in mice. The C-terminal acidic serine aspirate rich MEPE (ASARM) motif of the MEPE protein can be cleaved by proteolytic activity of cathepsin B. The proteolytic cleavage is protected by another enzyme, PHEX. The released ASARM motif circulates in the bloodstream to regulate reabsorption of phosphate in the renal proximal tubules and mineralization of the bones and teeth. For this reason, ASARM peptide is also called minhibin due to its bone mineralization-inhibiting action and phosphatonin due to its phosphate reabsorption- inhibiting action. DMP1 is a member of the SIBLING family, a group of non- collagenous extracellular matrix proteins involved in bone mineralization. These genes are localized to human chromosome 4q21-25. They have similar exon arrangements and include dentin sialoprotein, dentin phosphoprotein, osteopontin, integrin-binding sialoprotein, and matrix extracellular phosphoglycoprotein. DMP1 is highly expressed in osteocytes and is comprised of 513 residues, but is secreted in bone and dentin as 37 kDa N-terminal and 57 kDa C-terminal fragments from a 94 kDa full-length precursor. Potential roles for DMP1 in bone may include regulating hydroxyapatite formation, and depending upon proteolytic processing and phosphorylation, it may regulate local mineralization processes in vivo. In autosomal recessive hereditary rickets, the DMP1 gene is lost and subsequently causes impaired osteocyte differentiation and increased production of FGF23. OO has all of the classic biochemical and radiologic criteria of the hypophosphatemic osteomalacias. Diagnosis is, therefore, dependent on a diligent search for tumors in all patients with hypophosphatemic vitamin-D resistant osteolamacic disease. Tumors may range from small to large and from benign to malignant. Moreover, the tumor may be present for many years before diagnosis. The first and foremost treatment of OO is complete resection of the associate tumor. However, recurrence of mesenchymal tumors, such as giant cell tumors of bone, or the inability of complete resection of certain malignancies, such as prostatic carcinoma, has resulted in the need for therapeutic intervention. Conclusion(s): This case dealt with the unusual histologic features of a bone tumor leading to the diagnosis of OO. Initially, it was misinterpreted as chondromyxoid fibroma of metatarsal bone. However, after a thorough review of the case, this instance was recognized as a phosphaturic mesenchymal tumor of the mixed connective tissue variant. This case demonstrates that as pathologists, in order to reach the correct diagnosis, we should not rely solely on microscopic findings but should also carefully evaluate the clinical findings. References: McCance RA: Osteomalacia with looser's nodes (milkman's syndrome) due to a raised resistance to vitamin D acquired about the age of 15 years. 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