DIAGNOSIS: PHOSPHATURIC MESENCHYMAL TUMOR (MIXED CONNECTIVE TISSUE VARIANT) OF THE CAVERNOUS SINUS.
Oncogenic osteomalacia (OO) is an acquired syndrome characterized by phosphaturia, hypophosphatemia, normal serum calcium levels, and decreased levels of 1,25-dihydroxyvitamin D3 (6,9,10,11). These metabolic disturbances are associated with a tumor and improve or completely disappear after its removal (6,9,10,11). OO was initially described by McCance et al. (3), 1947, however Prader et al. (4) were the first to infer a tumor as the causal factor (4).
OO usually affects adults, without a gender predominance (6,11). The peak incidence is in the 4th decade (mean, 33 years, range 5 to 63), however the diagnosis of the causative tumor is usually later on the 4th to 6th decades (11). Symptoms are associated with the hypophosphatemic metabolic state and the most frequently reported are bone and muscle pain, severe muscle weakness, fractures, height loss, gait disturbances, skeletal deformity, and slow growth (6,11). Tumors causing OO usually occur in bones and soft tissues, and less frequently in skin (10,11) or breast (2). Despite the fact that their occurrence in the head and neck region is fairly common (5,11), only one case affecting the central nervous system (CNS) has been reported so far (5), in which the tumor arose in the ethmoid sinus and extended into the frontal lobe.
OO is caused by a spectrum of mesenchymal tumors usually located in soft tissues (intramuscular) or bones. Other neoplasms, including breast carcinoma, prostate carcinoma, small cell carcinoma, multiple myeloma, and lymphocytic leukemia have rarely been reported in association with this syndrome (6,11). To the best of our knowledge this is the first case of a dural-based phosphaturic mesenchymal tumor reported.
Despite the protean histological appearances of these tumors, Weidner (11) and Weiss & Goldblum (12) suggested that they are distinctive enough to warrant a separate designation. Weidner and Santa Cruz (10) carried out the most comprehensive histological analysis of these neoplasms. According to their observations, these tumors have features that remarkably resemble those observed in hemangiopericytomas (11), including osteoclastic-like multinucleated giant cells (87% of the cases) and prominent vascularity (80% of the cases) (10,11). Weidner and Santa-Cruz (10) developed a 4-tiered classification system for tumors associated with OO: 1) primitive-appearing mixed connective tissue tumors; 2) osteoblastoma-like tumors; 3) non-ossifying fibroma-like tumors; 4) ossifying fibroma-like tumors (10,11). Neoplasms included in the first category were the most frequent and showed unique morphological features being characterized by primitive-appearing stromal cells, variably prominent vessels with hemangiopericytic pattern, osteoclastic-like giant cells, foci of microcystic changes, osseous metaplasia, and poorly defined chondroid islands (6,10,11). Neoplasms included in the other categories resembled their homonymous bone tumors (6,10,11). These authors also suggested that tumors included in the first category should be labeled as "phosphaturic mesenchymal tumor (mixed connective tissue variant)" when dealing with tumors included in the first category (10,11); for those resembling osteoblastoma, an appropriate term would be "phosphaturic mesenchymal tumor (osteoblastoma-like variant)"; other tumors should have similar designations (10,11).
In accordance with previous studies (6,10,11), the immunohistochemical profile of our case showed vimentin positivity and lacked the expression of any lineage-specific marker. Based on the morphological and immunohistochemical features of the neoplasm, as well as on the marked improvement of the hypophosphatemic metabolic state and clinical symptoms after tumor resection, we consider our case a typical example of a tumor included in the first group of phosphaturic mesenchymal tumors of Weidner and Santa Cruz´s classification (10).
Since the initial description of phosphaturic tumors and OO, it has been thought that a specific substance (phosphatonin) would be secreted by tumor cells (8), however its chemical nature remained unknown until recently (8). In 2001, Shimada et al. (7) and White et al. (13) described the production of fibroblast growth factor 23 (FGF23) by tumors causing OO. FGF23, a secreted member of the fibroblast growth factors, is the protein product of the gene mutated in the autosomal dominant hypophosphatemic syndrome (ADHS). There is compelling evidence to suggest that FGF23 plays a major role in the impairment of renal tubular reabsorption of phosphate, either acting directly or through a second metabolic messenger on renal tubular cells (8).
The location, radiological findings and morphology of our case could lead to a misdiagnosis of hemangiopericytoma (12) or one of its rare variants (i.e., lipomatous hemangiopericytoma), since scattered adipocytic islands were observed in the tumor (1,12). However, osteoclastic-like multinucleated giant cells and hyalinized thick-walled vessels are not usual features of hemangiopericytomas (1,11,12). Moreover, CD34 is positive in the majority of hemangiopericytomas (1,12) and was negative in the present case.
It is of utmost importance that pathologists should be aware of the clinical symptoms and metabolic status of the patients to achieve a correct diagnosis of phosphaturic mesenchymal tumor. We conclude that in patients with idiopathic hypophosphatemia, hyperphosphaturia, and normal serum calcium levels, a meticulous search for a causative tumor, even in odd locations (i.e., central nervous system), is highly rewarding (6,10,11), because surgery may lead to cure or marked improvement of patients´ symptoms.
Contributed by Jorge S Reis-Filho, MD, Maria E Paiva, MD and José M Lopes, MD, PhD