Pathologic Quiz Case: A 36-Year-Old Woman With Muscle Pain and Weakness

A 36-year-old white woman was admitted to our hospital for investigation of muscle pain and weakness of long duration. No specific neurologic deficits were observed. Laboratory workup disclosed a moderate hypophosphatemia (1.8 mg/dL; normal, 2.5–4.5 mg/dL), elevated serum alkaline phosphatase activity (428 IU/dL; normal, 30–115 IU/dL), and normal serum calcium levels (8.7 mg/dL; normal, 8.0 to 11.0 mg/dL). Moreover, there was a marked hyperphosphaturia (daily urinary excretion of phosphate = 1.770 mg). After an extensive clinical and radiological workup, radiography disclosed a 4-cm tumor on the sole of the left foot. Magnetic resonance scans showed a 4-cm intramuscular soft tissue tumor with smooth nodular margin (Figure, A). No evidence of other neoplasm was observed even after extensive clinical and radiological workup. A surgical excision of the tumor was performed. During the first week after the surgical resection, clinical symptoms disappeared, and the patient's serum phosphate level increased to a normal level (2.9 mg/dL).The gross specimen consisted of a well-circumscribed, hard nodule with a heterogeneous yellow to whitish cut surface with scattered brownish areas. Histologic examination showed a heterogeneous neoplasm composed of (1) plump spindle-shaped mesenchymal cells with ill-defined eosinophilic cytoplasm and vesicular nuclei with occasionally distinctive nucleoli arranged in interlacing fascicles (Figure, B) and (2) sheets of epithelioid cells with deeply eosinophilic cytoplasm and well-defined borders. In the spindle cell foci, there was a prominent vascular component composed of small to medium-sized branching vessels. Foci of microcystic changes, osteoclastic-like multinucleated giant cells, hemorrhage, and hemosiderin deposits were observed within both the spindle and the epithelioid components (Figure, C and D inset). Large islands of chondroid metaplasia were evident (Figure, D). Discrete foci of osseous metaplasia were found, mainly at the peripheral aspects of the tumor. The spindle-shaped neoplastic cells were immunoreactive for vimentin and α-smooth muscle actin; the epithelioid cells reacted with CD68 and focally with S100 protein. In addition, the osteoclastic-like giant cells showed strong cytoplasmic positivity for CD68. Reactions for antibodies against cytokeratins, desmin, CD34, and HMB-45 were all negative.What is your diagnosis?Oncogenic osteomalacia (OO), or tumor-induced osteomalacia-rickets, is a rare clinicopathologic syndrome that is characterized by renal phosphate wasting (hyperphosphaturia), hypophosphatemia, normal serum calcium levels, and decreased serum 1,25-dihydroxyvitamin D3 levels, which are induced by a neoplastic lesion and disappear completely after its resection.1–4 McCance5 was the first to describe this syndrome, and Prader et al6 were the first to recognize a neoplasm as the cause of the clinical signs and symptoms of OO.Oncogenic osteomalacia usually affects adults of both sexes, with a peak incidence in the fourth decade (mean, 33 years; range, 5–63 years)2; however, the causative tumor is usually diagnosed later in the fourth to sixth decades.2,4 Most patients present with bone and muscle pain, as well as severe muscle weakness.1,2,4 Other complaints include fractures, height loss, gait disturbances, skeletal deformity, and slow growth.1–4 Most of the tumors causing OO occur in bones and soft tissues, and, less frequently, in skin1,2 and breast7; they arise more frequently in the lower extremities, head and neck region, and upper extremities.1–2,4 Oncogenic osteomalacia is thought to be a rare disease, but the true incidence of this syndrome may be underestimated because in several cases the tumor is small and in an odd location,1,2,4 which makes recognition difficult.Most cases of OO are caused by a mesenchymal tumor, and other neoplasms, including breast carcinoma, prostate carcinoma, small cell carcinoma, multiple myeloma, and lymphocytic leukemia, have rarely been reported in association with OO.2,4 The archetypal neoplasms associated with this syndrome are located in soft tissue (intramuscular) or bones.1,2,4 The pathologic diversity of these tumors reflects the great variability of the histologic diagnostic terms used to classify them. According to Weidner,2 most of these tumors show osteoclastic-like multinucleated giant cells and have prominent vascularity. Weidner and Santa Cruz1 collected 17 cases of mesenchymal tumors causing OO and proposed the most widely accepted classification for this group of neoplasms, as follows: (1) primitive-appearing mixed connective tissue tumors; (2) osteoblastoma-like tumors; (3) nonossifying fibroma-like tumors; and (4) ossifying fibroma-like tumors.1,2 In their review,1 10 of 17 cases were examples of the first category; these tumors were composed of primitive-appearing stromal cells, variably prominent vessels with hemangiopericytic pattern, and osteoclastic-like giant cells, as well as foci of microcystic changes, osseous metaplasia, and poorly defined chondroid islands.1,2 Most of the cases in this group occurred in the soft tissues. Only 1 tumor behaved in a malignant fashion with local recurrence and lung metastasis; all other cases were benign.1,2 Tumors from the other 3 groups showed remarkable similarities with common bone tumors.1,2 As expected, they arose more frequently in bones, and all pursued a benign course.1,2 For the sake of simplicity and comprehension, Weidner and Santa Cruz1 suggested that these tumors be labeled by the phrase phosphaturic mesenchymal tumor (mixed connective tissue variant) for the first group; for those tumors resembling osteoblastoma, phosphaturic mesenchymal tumor (osteoblastoma-like variant), and so on.1,2 Our case showed the typical histologic appearance of tumors included in the first group of Weidner and Santa Cruz´s classification,1,2 including primitive-appearing mesenchymal cells, multinucleated osteoclastic-like giant cells, prominent vascularity, microcystic areas, and foci of chondroid and osseous metaplasia. Based on these histologic findings and on the complete remission of the metabolic changes after tumor resection, we considered the tumor to be the cause of the OO and labeled it phosphaturic mesenchymal tumor (mixed connective tissue variant).Immunohistochemical analysis of the previously reported neoplasms associated with OO usually showed only vimentin positivity.1,2 In our case, we observed focal immunoreactivity for α-smooth muscle actin in the spindle cell component, CD68 and focal S100 protein positivity in the epithelioid cells, and CD68 positivity in the osteoclastic-like multinucleated giant cells.Since the initial descriptions, several hypotheses have been raised regarding a putative secreted substance that could be the culprit in OO, which has been named phosphatonin.8 Recently, a breakthrough in the comprehension of OO was reported. Shimada et al9 and White et al10 elegantly described the production of fibroblast growth factor 23 (FGF23), a novel secreted member of the fibroblast growth factors, by tumors of OO.8–10 Interestingly, FGF23 is the protein product of the gene mutated in the autosomal dominant hypophosphatemic syndrome.8Pathologists and clinicians must be aware of the clinical laboratory and anatomic pathology features of OO in order to avoid a delay in diagnosis. We stress that in patients with idiopathic hypophosphatemia, hyperphosphaturia, and normal serum calcium levels, a meticulous and continuous search for a causative tumor is worthwhile.1,2,4 Even odd locations must be investigated, as a complete cure is achieved once the tumor is resected.1,2,4