Brain Pathology Case of the Month - October 2009

DIAGNOSIS   Phosphaturic Mesenchymal Tumor, Mixed Connective Tissue Variant (PMT-MCT)


Osteomalacia is a bone disease characterized by gradual softening and bending of the bones due to inadequate mineralization of osteoid. The most common etiologies of osteomalacia include vitamin D deficiency and renal tubular dysfunction; however, in rare instances, osteomalacia can be associated with bone and soft tissue tumors as a paraneoplastic syndrome (i.e. oncogenic osteomalacia) (1, 4, 8). Though the mechanism behind the inadequate mineralization of osteoid in this setting is not entirely understood, it is hypothesized that tumor over-expression of FGF-23 may play a role. This protein appears to inhibit trans-epithelial phosphate transport in renal tubules, resulting in renal phosphate wasting and subsequent osteomalacia (2-4, 11). While a heterogeneous group of tumors may cause oncogenic osteomalacia, PMT-MCT is the most common (1, 6).

Tumors associated with oncogenic osteomalacia are commonly misdiagnosed as other bone and soft tissue tumors such as hemangiopericytoma, hemangioma, giant cell tumor, and osteoblastoma (6). In 1987, Weidner and Santa Cruz coined the term "phosphaturic mesenchymal tumor, mixed connective tissue variant," effectively classifying these lesions as a distinct clinicopathologic entity (10). In spite of this important contribution, many clinicians and pathologists were unaware of the existence of PMT-MCT following this publication. In 2004, Folpe et al published a review of a large number of oncogenic osteomalacia-associated tumors and further defined the histopathologic and immunophenotypic characteristics of these lesions (1).

PMT-MCT may not be easily recognized because of its rarity and polymorphic histologic features. Classic histopathologic characteristics include bland spindle cells with small nuclei surrounded by a myxochondroid and osteoid-like "smudgy" matrix. Other characteristic features include areas of flocculent calcification, osteoclast-like giant cells, and a well-developed capillary network (1). Examples that do not show the entire morphologic spectrum of PMT-MCT are more difficult to recognize. The index case showed classic PMT-MCT features. In conjunction with an appropriate clinical presentation and laboratory findings, the diagnosis of PMT can often be made on H&E sections; ancillary immunostains with antibodies against FGF-23 and dentin matrix protein 1 (DMP1) are also helpful in confirming the diagnosis (1, 9).

Patients with PMT-MCT commonly have a long protracted history of bone pain and multiple fractures. Laboratory investigations typically reveal hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase activity, and low or inappropriately normal serum 1,25-dihydroxyvitamin D3 levels. Patients also fail to respond to vitamin D therapy (1, 4, 8). Although uncommon, nonphosphaturic variants of PMT-MCT are also thought to exist, so the absence of signs and symptoms of osteomalacia should not entirely eliminate PMT-MCT from the differential diagnosis (1). Lesions are often inapparent due to their small size and slow growth, and detecting a tumor often requires an in-depth clinical and radiological examination. The patient in this case exhibited hypophosphatemic osteomalacia for six years before the responsible tumor was identified despite a thorough work-up and numerous radiological studies. This clinical scenario is common in most cases of PMT-MCT, as described in numerous previously reported cases (1, 2, 6).

Complete surgical resection of the tumor is curative, resulting in rapid correction of metabolic abnormalities and eventual resolution of symptoms associated with osteomalacia (1, 2, 4, 8), as was seen in this case. At the time of resection, the patient's serum phosphorus level was 1.1 mg/dL and urine phosphorus was 198.5 mg/dL. At follow up approximately two months later, her serum and urine phosphorus levels had both returned to normal (4.3 mg/dL and 47.9 mg/dL, respectively) as did serum FGF-23 levels.

PMT-MCT can originate in the bone or soft tissue of any location, although the extremities or appendicular skeleton account for most cases (1, 6). Reported cases of PMT-MCT occurring in the axial skeleton are very rare. Folpe et al. reported two examples: one in the sacrum and one in the first cervical (C1) vertebra. They also cited two previously reported cases: one by Stone et al. located in the thoracic spine (T3-T4) and originally diagnosed as a neuroendocrine tumor, and the other reported by Yu et al. involving the cervical spine (C2) (1, 7, 12). Furthermore, Reis-Filho et al. reported a case of PMT-MCT occurring in the cavernous sinus. Similar to our case, this patient presented with a protracted history of osteomalacia and hypophosphatemia, and surgical resection was curative. In addition to the morphologic features described in that case, the case described herein displayed a wider morphologic spectrum of PMT-MCT including the characteristic osteoid-like matrix, dystrophic calcification, and ossification (5).

Even though PMT-MCT is a rare tumor and occurs infrequently in the axial skeleton (1), the surgical neuropathologist may occasionally encounter a case like the one described herein. Awareness of the existence of PMT-MCT as a distinct clinicopathologic entity is crucial for optimal patient outcome since complete surgical resection without additional treatment is curative. Therefore, PMT-MCT should be added to the differential diagnosis of spinal and paraspinal lesions.

Presented, in part, at the 85th annual meeting of the American Association of Neuropathologists, San Antonio, Texas, June 11-13, 2009.


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Contributed by Ann E. Marshall, Sarah E. Martin, Narasimhan P. Agaram, Jey-Hsin Chen, Eric M. Horn, Annette C. Douglas-Akinwande, Eyas M. Hattab

International Society of Neuropathology