Original contributionPhosphaturic mesenchymal tumors show positive staining for somatostatin receptor 2A (SSTR2A)☆
Introduction
Tumor-induced osteomalacia (TIO; also previously referred to as “oncogenic osteomalacia”), refers to a paraneoplastic syndrome in which there is inadequate mineralization of mature bone, that is, secondary osteomalacia. The syndrome is caused by tumors that secrete phosphaturic hormones, most notably fibroblast growth factor 23 (FGF23) [1], [2], [3], [4], [5], [6], [7]. FGF23 inhibits both renal tubular phosphate reabsorption and conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D and therefore in excess leads to renal phosphate wasting, hypophosphataemia, and low or low-normal serum 1,25-dihydroxyvitamin D levels.
TIO typically presents with muscle weakness, bone pain and recurrent fractures [8]. Although elevated serum FGF23 in the presence of hypophosphatemia and renal phosphate wasting is very suggestive of TIO, there is often a long delay between first presentation and consideration of this diagnosis [9]. Furthermore, even when the diagnosis of TIO is suspected, the causative tumor is commonly difficult to identify because it may be small and slow growing. Once discovered, complete removal or ablation of the tumor results in rapid correction of the clinical and biochemical abnormalities [10], [11], [12].
In 2004 Folpe et al [1] demonstrated that the majority of tumors that cause TIO (24 of 29; 83%) show distinctive morphological features (Fig. 1). They termed this entity “phosphaturic mesenchymal tumor mixed connective tissue variant" and it is now more commonly known just as “phosphaturic mesenchymal tumor" (PMT). The characteristic histological features of PMTs include the presence of bland spindled cells, myxoid and microcystic change, a prominent hemangiopericytomatous vascular pattern and the presence of a peculiar “grungy" pattern of calcification [1], [9], [13], [14]. However, these diagnostic histological features are not present in all tumors that cause TIO and, when present, may be subtle and particularly difficult to appreciate on small biopsies. Therefore, it would be clinically useful to have a readily available diagnostic marker that confirms the diagnosis of PMT in a patient with suspected TIO or alternatively, to suggest the diagnosis of TIO when a tumor with morphology compatible with PMT is encountered in a patient in which TIO is not suspected clinically.
The identification of FGF23 production by tumor cells either by immunohistochemistry or by RT-PCR on formalin-fixed paraffin-embedded tissue has been used to confirm the diagnosis of PMT [1], [3], [4], [15]. However neither immunohistochemistry nor RT-PCR for FGF23 is widely available in diagnostic surgical pathology laboratories. Furthermore FGF23 lacks specificity for the diagnosis of the causative tumors of TIO. Although FGF23 production has been reported in 16/17 (94%) of PMTs with osteomalacia, it is also found in up to 75% of tumors with similar morphology that are not associated with osteomalacia [15]. Furthermore using the extremely sensitive method of RT-PCR, FGF23 production has also been reported in 7 of 16 (44%) otherwise typical aneurysmal bone cysts and 2 of 7 (29%) chondromyxoid fibromas without clinical evidence of phosphate wasting or osteomalacia [16]. Therefore, although demonstration of FGF23 by immunohistochemistry or RT-PCR is quite sensitive, its clinical utility is limited by its poor specificity and lack of widespread availability.
Although FGF23 is part of an endocrine loop involving osteocytes, the kidney and other organs, most pathologists do not think of PMTs as being neuroendocrine tumors. Given their endocrine nature it is perhaps not surprising that PMTs have been successfully identified and localized by functional imaging more commonly used to identify neuroendocrine tumors such as octreotide scintigraphy [17], [18] or, more recently, positron emission tomography using gallium-68 DOTATATE and computed tomography (gallium-68 DOTATATE PET/CT) [9]. These imaging modalities are based on the expression of somatostatin receptors. Immunohistochemistry for the somatostatin receptor 2A (SSTR2A) has in turn been shown to correlate with neuroendocrine tumor somatostatin receptor expression quantified by in vitro autoradiography [19] and with positivity by gallium-68 DOTATATE PET/CT [20].
We therefore sought to test the hypothesis that immunohistochemistry for SSTR2A using a commercially available rabbit monoclonal antibody could be used to support the diagnosis of PMT in the routine surgical pathology laboratory.
Section snippets
Materials and methods
All cases of definite TIO encountered at the Royal North Shore Hospital in Sydney Australia and the Centre Leon Berard in Lyon France were identified by searching the appropriate databases and medical records. Inclusion criteria for a definite case of TIO required hypophosphatemia/renal phosphate wasting and osteomalacia associated with a tumor with cure or biochemical remission occurring after tumor removal or ablation. As controls, a range of tumors in the potential clinical or pathological
Results
Paraffin blocks were available from 15 tumor samples (from 14 patients, one with a local recurrence) definitely associated with the clinical syndrome of TIO. Of these cases, 8 have been previously reported [4], [9], [21]. The clinical, demographic and immunohistochemical features are summarized in Table 1. Briefly, 7 patients were male and 7 were female. Their ages ranged from 31 to 73 (mean 52 years). Thirteen of the tumors arose within bone (glenoid, tibia, femur, foot, pubis, acetabulum,
Discussion
Building on the work of Weidner and Santa Cruz [22], Folpe et al’s demonstration that most tumors associated with TIO show stereotypical histological features allowed recognition of PMT as a distinct clinicopathological entity [1]. These typical histological features include the presence of bland spindle cells, well-developed capillary networks and an osteoclastic reaction. Perhaps most distinctively there is usually a peculiar pattern of “grungy" calcification and a striking
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Funding and conflict of interest disclosures: This study was partially funded through the Northern Translational Cancer Research Unit Fellowship awarded to MH. The authors report no conflict of interest.