<div>Abstract</div><div>Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome
characterized by renal phosphate wasting, which leads to deranged bone
turnover. TIO is usually associated with benign mesenchymal tumors,
although it has also been reported in malignant tumors. We report the
case of a 56-year-old individual who presented with a long clinical
course of hypophosphatemia, weakness, and kyphosis, associated with a
tumor in the foot. After several years, this lesion exhibited malignant
behavior and was diagnosed as a high-grade sarcoma. To date, this case
is among the 10 reported cases in the literature of a mesenchymal tumor
associated with TIO undergoing malignant transformation. This report
underscores the importance of a comprehensive evaluation of patients
with unexplained hypophosphatemia, and highlights the need for diligent
follow-up to detect possible malignant transformation of the underlying
tumor. Clinicians should consider TIO in the differential diagnosis of
hypophosphatemia, and promptly investigate for the presence of an
underlying tumor, as early detection may improve the patient’s
prognosis.</div><div>Key words: Oncogenic osteomalacia, Case Reports, Paraneoplastic
Syndromes, Rickets, Sarcoma</div><div>Introduction</div><div>Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia,
is a rare paraneoplastic syndrome that was first described by McCance in
1947 (1). This condition is characterized by renal phosphate wasting,
leading to disrupted bone turnover. Clinically, TIO presents with
symptoms such as muscle weakness, bone pain, and fractures.
Biochemically, TIO is marked by hypophosphatemia, hyperphosphaturia,
normal or low levels of 1,25-dyhydroxi-vitamin D, elevated alkaline
phosphatase, normal levels of calcium and parathyroid hormone (PTH), and
notably high levels of fibroblast growth factor 23 (FGF23) (2,3). The
exact incidence of TIO is not precisely known, but one of the largest
studies in Denmark reported it to be below 0.13 per 100,000 person-years
for the total population investigated (4). Tumors responsible for TIO
are highly heterogeneous, but it is typically induced by mesenchymal
tumors originating from soft tissue or bone. Recently, the World Health
Organization has recognized phosphaturic mesenchymal tumors (PMT) as
morphologically distinctive neoplasms that cause TIO (5). The majority
of tumors causing TIO are PMTs, followed by hemangiopericytoma, giant
cell tumor, and hemangioma. Only 10% of the tumors in a systematic
review were found to be malignant, highlighting the rare occurrence of
malignancy in TIO cases (6). Due to the rarity of this condition, the
limited knowledge about the disease, and the unpredictable behavior of
the underlying tumor, a definitive diagnosis may take years to
establish.</div><div>Case report</div><div>A 56-year-old man with hypertension presented with a six-year history of
lumbar pain. Several months before his initial assessment, he developed
progressive weakness in his lower extremities, leading to total
disability. During the physical examination, the patient was bedridden,
had a short stature, marked kyphosis, and generalized muscle weakness.
His muscular reflexes were diminished, and there was no evidence of
neuropathic involvement. Laboratory tests showed a normal complete blood
count, preserved renal and hepatic function, negative serologic
screening, and negative autoantibodies. A metabolic panel was ordered,
revealing an elevation of alkaline phosphatase (543 IU/L), severe
hypophosphatemia (phosphorus 1.0 mg/dL), and normal calcium levels
(calcium 9.1 mg/dL). PTH levels were slightly above the normal range (57
pg/mL), and vitamin D levels were low (8 pg/mL). A 24-hour phosphorus
excretion was 860 mg, and the fractional excretion of phosphorus was
51%, consistent with urinary phosphorus wasting in the context of
hypophosphatemia. Urine analysis did not show any features of proximal
tubule dysfunction. Hereditary rickets was unlikely given the patient’s
age and lack of family history; instead, FGF23-dependent
hypophosphatemia as a paraneoplastic syndrome was suspected, and a tumor
localization work-up was initiated. Previous chest X-ray and
thoraco-abdominal CT, were normal. A whole-body bone scintigraphy with
technetium-99m-hydroxy-methylene-diphosphonate (TC99-HMDP) was ordered,
revealing heterogeneous involvement of the maxilla, mandible, multiple
ribs, right radius, sacrum, iliac, tibia, and bilateral calcaneus.
Increased asymmetric uptake was observed in the right foot, so
Tc99-Octreotide single photon emission computed tomography (SPECT/CT)
and magnetic resonance (SPECT/MR) were performed, revealing a
hypodense/hypointense localized lesion in the astragalus with lytic
behavior, sclerotic border, and significantly increased metabolism,
consistent with a mesenchymal tumor (Figure 1). The patient was referred
for a surgical oncology consultation, but unfortunately, he was lost to
follow-up.</div><div>One year later, he returned to our clinic reporting a weight loss of 23
kg over the last three months and an exophytic tumor in the same region
where the previous imaging studies had revealed abnormal uptake of
Tc99-Octreotide (see Figure 2). A new chest CT scan showed multiple
nodular lesions in the lungs, which were compatible with metastases.
Histopathological analysis with immunohistochemistry of the foot tumor
confirmed a diagnosis of high-grade sarcoma with fusiform, epithelioid,
and pleomorphic patterns (Figure 3). The patient began receiving
oncologic treatment with a dose-adjusted AIM regimen (doxorubicin,
ifosfamide, mesna). Unfortunately, he had an adverse clinical course and
died within the next two months.</div><div>Discussion</div><div>TIO is a paraneoplastic syndrome characterized by the excessive
expression of FGF-23. As a consequence, FGF-23 mediates the
internalization of the sodium-phosphate cotransporter (NaPi) in renal
tubular cells, leading to impaired reabsorption of phosphate by the
kidneys. Moreover, FGF-23 inhibits the enzymatic hydroxylation of
25-hydroxyvitamin D in the kidneys, resulting in inadequate production
of active 1,25-dihydroxyvitamin D, ultimately contributing to the
pathogenesis of osteomalacia (7,8). Furthermore, FGF-23 in TIO can
impact bone mineralization through indirect mechanisms. It has been
shown to suppress the production of PTH. TThis reduction in PTH levels,
mediated by FGF-23, hampers the release of calcium from bone, thereby
exacerbating the mineralization abnormalities observed in TIO-induced
osteomalacia (9). Furthermore, FGF-23 represses the transcription of the
alkaline phosphatase gene, subsequently resulting in a diminished
function of tissue-nonspecific alkaline phosphatase (TNALP) at the cell
membrane. This inhibition results in a reduction in the breakdown of
inorganic pyrophosphate, leading to decreased phosphate levels. In
addition to this, osteopontin (OPN), a protein vital to the process of
bone mineralization, has its production and release stimulated by
extracellular phosphate. As such, through the suppression of TNALP gene
transcription, FGF-23 indirectly attenuates the secretion of OPN, thus
further modulating bone mineralization processes (10,11).</div><div>Symptoms of TIO often persist for months or even years before a
diagnosis is made. The initial symptomatology predominantly comprises
musculoskeletal discomfort, including diffuse muscle pain and
progressive weakness, often leading to substantial impairment in the
patient’s mobility and quality of life. As the disease advances, it
progressively impacts the skeletal system, resulting in debilitating
bone pain. Furthermore, due to the decreased mineralization and
consequent weakening of the bone structure, patients with TIO frequently
experience pathological fractures. These fractures occur in bones under
normal physiological stresses, highlighting the profound degree of bone
fragility associated with this condition (12,13).</div><div>TIO indeed represents a rare and unique disease entity. Although it
predominantly manifests in middle-aged adults, it bears the potential to
present across all age groups without displaying a particular gender
predilection (14,15). As stated previously, it is associated with benign
mesenchymal tumors in the vast majority of cases, approximately 90%
(3). Yet, it is well-documented that malignant tumors, most notably
sarcomas, also have the capacity to induce this condition (15–18)</div><div>In cases lacking an initial biopsy, as in the patient under discussion,
it becomes challenging to conclusively determine the tumor’s original
nature. It remains uncertain whether the initial tumor was benign and
subsequently underwent malignant transformation, or if the neoplasm was
inherently sarcomatous. Given the patient’s extended history of
hypophosphatemic symptoms spanning six years, the radiologic findings on
the 99mTc-Octreotide Scintigraphy with SPECT/CT, and the abrupt onset
and rapid progression of signs indicative of malignancy, including
metastatic disease and substantial weight loss over a three-month
period, the likelihood of malignant transformation is substantially
high.</div><div>The presentation of our patient, characterized by the manifestation of a
localized mesenchymal tumor in the foot subsequently diagnosed as a
high-grade sarcoma one year post TIO identification, brings to the fore
the criticality of considering TIO in the differential diagnosis of
unexplained hypophosphatemia. This case underscores the potential for
malignant transformation within the clinical course of TIO, thereby
emphasizing the imperative nature of vigilant longitudinal follow-up.
Such conscientious monitoring is paramount in early detection of
malignant transformation, thereby facilitating timely and appropriate
therapeutic interventions, significantly impacting patient prognosis and
the management of this complex disease.</div><div>Disclosure and funding statements</div><div>We declare that we have no conflict of interest and did not receive
funding for the elaboration of the manuscript.</div><div>References</div><div>1. McCANCE RA. Osteomalacia with Looser’s nodes (Milkman’s syndrome) due
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with significantly increased metabolism.</div><div>Figure 2. Exophytic tumor in the right foot.</div><div>Figure 3. H&amp;E. Malignant mesenchymal neoplasm with spindle cells and
epithelioid patterns.</div>