Answer

Phosphaturic mesenchymal tumor (PMT) with tumor-induced osteomalacia (TIO) and insufficiency-type stress fractures.

Discussion

Phosphaturic mesenchymal tumors (PMTs) are rare, with about 450 reported cases in the medical literature [1]. They were first identified and named in 1987 by Weidner and Santa Cruz, who recognized them as a cause for osteomalacia and rickets [2]. PMTs are typically diagnosed in people aged 40–45 years, with no gender preference [3]. The incidence rate is low, at about 0.04 to 0.13 cases per 100,000 people per year [4, 5]. Most cases (95%) affect the extremities [6]. While PMTs are generally benign, rare malignant variants have also been reported [7].

PMT cells secrete a hormone-like peptide called fibroblast growth factor-23 (FGF23)—a phosphotropic hormone produced by osteocytes that affect bone metabolism and mineralization on a few fronts [8]:

  1. 1.

    Suppresses expression of sodium-phosphate cotransporters in proximal renal tubules, which reduces serum phospate.

  2. 2.

    Hinders the activity of 1-α-hydroxylase, a crucial enzyme in synthesizing 1,25-dihydroxy vitamin D3, which affects calcium and phosphate reabsorption.

  3. 3.

    Demonstrates an inhibitory effect on parathyroid hormone (PTH) secretion.

  4. 4.

    Inhibits bone mineralization.

Cumulatively, FGF23 leads to the rare paraneoplastic syndrome of tumor-induced osteomalacia (TIO)/oncogenic osteomalacia, and patients may experience bone pain due to insufficient osteomalacic fractures.

Identifying PMTs can be difficult because of their vague symptoms, small size, slow growth, and location. Diagnostic latency can range from 2.9 to 28 years [9]; therefore, having a high level of clinical suspicion can be helpful in diagnosis.

Biochemically, individuals with PMTs may exhibit regular kidney function, higher levels of FGF23, elevated alkaline phosphatase, reduced levels of 1,25-dihydroxy Vitamin D3, and hypophosphatemia [10].

Radiographic findings of TIO include osteopenia, coarse trabeculae, thin cortices, and—most notably-- insufficiency-type stress fractures.

In more than 96% of cases, PET-CT with somatostatin analog can accurately identify the location of the tumor [11, 12]. A newer method called 68 Ga-DOTA-TOC-PET/CT-scan, uses an acid called DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) to bind with a derivative of octreotide called (Tyr3)-octreotate, has proven to be the most sensitive in detecting underlying PMTs [13, 14].

PMTs may present with a varied imaging appearance on MRI [15].

Histologically, PMTs typically comprise a variably cellular, cytologically bland, spindled, or stellate cellular proliferation, usually with a prominent vascular network. A distinctive smudgy basophilic myxoid or myxochondroid matrix with smudgy calcifications is usually present. Osteoclast-like giant cells, fibrohistiocytic spindled cells, microcystic changes, adipose tissue, or peripheral mature bone may be present. Rare cases display malignant histologic features [16].

Surgical resection typically has a good outcome; symptoms and serum phosphate levels should return to normal within 5 to 10 days, while bony healing time can vary [17]. Monitoring serum phosphate levels every six months and continuing with long-term follow-up is important to watch for potential recurrence [18].

At two-year follow-up, our patient's fractures healed.

In summary, PMTs are rare tumors that cause FGF23 overproduction, resulting in hypophosphatemia, TIO, and insufficiency-type stress fractures that can be corrected with complete excision. Most PMTs are benign, but malignant PMTs can also occur. While the appendicular skeleton is the most common site, PMTs may rarely occur in the axial skeleton and other locations. A practical stepwise diagnostic approach can be venous sampling for FGF23 levels for detection, 68 Ga-DOTA-TOC-PET/CT-scan for functional localization, and MRI for detailed anatomic characterization.