Summary: The patient is a 40-year-old woman who had been a very healthy
jogger. Five years previously, she had separated from her husband.
Since her separation, she had begun developing fractures. Although
the marital separation had nothing to do with the disease,
orthopedic surgeons who were treating her fractures thought she had
a case of Munchausen syndrome and referred her to psychiatrist. The
psychiatrist referred her to an endocrinologist for a metabolic
work-up. The patient was found to have increased urinary and
decreased serum phosphorus. When she presented to our institution,
she was so incapacitated that she had already arranged for a room
in a nursing home for assisted living.
Tumor-induced osteomalacia (TIO) (also known as oncogenic
The histopathologic analysis revealed that the metatarsal lesion
was a mesenchymal tumor. The resection of the tumor cured her
osseous abnormalities. Soon after surgery, she recovered, resumed
her normal life, and went back to jogging.
Multiple bony deformities that were suggestive of old malunited
fractures that involved the left humerus, rib cage, and spine were
noted on a technetium (Tc)-99m methylene diphosphate (MDP)
whole-body bone scan (Figure 1). The presence of a small radiodense
lesion in the left foot was detected by on an indium-111 (In-111)
OctreoScan (Covidien, Hazelwood, MO), which indicated the
possibility of a tumor (Figure 2). A plain X-ray of the left foot
revealed the cortical destruction of the second metatarsal bone in
the region of diaphysis (Figure 3). Magnetic resonace imaging (MRI)
of the left foot revealed a bone-destructive tumor that involved
the second metatarsal bone (Figure 4).
Oncogenic osteomalacia is an unusual syndrome that is
characterized by multiple biochemical abnormalities, such as
hypophosphatemia, hyperphosphaturia, and low levels of plasma
1,25-dihydroxyvitamin D. These abnormalities produce osteomalacia
in adults and rickets in children, which clinically manifest as
muscle weakness, bone pain, and multiple pathologic fractures. In
children, it can also lead to skeletal deformities, growth
retardation, and gait problems. Stress and insufficiency fractures
are prominent features. Tumors producing this syndrome secrete a
substance that inhibits the renal tubular reabsorption of
phosphates, which produces a cascade of biochemical abnormalities.
By virtue of this property, it belongs to the family of
paraneoplastic syndromes. It is interesting that all biochemical
and clinical features revert to normal when the tumor is
McCance2 is credited for having described the first
case in 1947, but in 1959 Prader3 and associates first
recognized the relationship between the tumor and the disease in an
11-year-old girl who developed rickets in association with giant
cell granuloma of a rib. All biochemical and clinical abnormalities
reverted to normalcy when the tumor was removed. They postulated
that the tumor produced a substance that acted like an antagonist
to vitamin D or as a phosphoric agent simulating parathyroid
hormone. It is now known that this unknown substance is of low
molecular weight and is termed phosphatonin.4
To date, >150 cases have been described sporadically in
different literatures, and, undoubtedly, many more cases have not
been reported. Awareness among the clinicians and the availability
of better diagnostic tools have increased the suspicion and the
detection of this condition.
The majority of these tumors are located in the extremities
(skin, muscles, bones) or around the head (paranasal sinuses), but
they may occur in almost any part of the body. These tumors are
slow growing and often remain hidden or undetected until clinical
features reach a fairly advanced stage. In one review of head and
neck tumors, the diagnosis of these tumors lasted a mean of 4.7
years from the onset of osteo-malacia.5 Often the
clinical presentation mimics X-linked hypophosphatemia (XLH) or
hereditary autosomal dominant hypophosphatemic rickets (ADHR).
Excessive paraneoplastic production of phosphatonin is thought to
be involved in the etiology of tumor-induced osteomalacia, whereas
impaired degradation and processing of phosphatonin due to
endopeptidase mutations (PHEX gene: phosphate-regulating gene with
homologies to endopeptidases on the X chromosome) is thought to
cause the typical findings in XLH. The fibroblast growth factor
(FGF)-23 gene is associated with ADHR. Both XLH and ADHR typically
present in childhood, although ADHR can present with variable or
delayed age of onset.
Tumors that cause TIO are often small, slow-growing, vascular,
and benign; they are associated with a variety of histologic types
and are commonly mesenchymal in origin. Hemangiopericytoma is the
most dominant histologic diagnosis noted in TIO. However, malignant
tumors have occasionally been reported. Based on their histologic
features, they have been sub-divided into 4 types: 1) phosphaturic
mesenchymal tumor, mixed connective tissue type (PMTMCT); 2)
osteoblastoma-like tumors; 3) ossifying fibroma-like tumors; and 4)
nonossifying fibroma-like tumors.6 Hemangiopericytoma is
the subtype of PMTMCT that comprises approximately 70% to 80% of
all tumors associated with TIO.7 Fibroblast growth
factor 23 belongs to the mesenchymal origin family, and the
measurement of serum FGF-23 has been found to be of considerable
importance in facilitating early diagnosis.
An important aspect of patient management is to locate the
tumor. CT and/or MRI (often followed by MR angiography) are the
main imaging tools used to determine tumor location. However,
whole-body CT and MRI have their own limitations. Nuclear
scintigraphy has emerged as a very useful and economical tool to
detect and determine the site of these tumors. Once the site is
identified, regional CT and/or MRI are performed to further
characterize the tumor. A Tc-99m MDP bone scan has been used as an
initial tool for the evaluation of the skeletal system. Diffuse
skeletal uptake often presents as a “superscan” with focal up-take
at sites of fractures. Multifocal lesions of increased activity
seen in skeletal scintigraphy of patients with acquired
hypophosphatemic osteomalacia may be misinterpreted as osseous
metastases. Gallium-67 is useful for imaging areas of infection,
inflammation, and tumors, including those tumors that induce
osteomalacia. Gallium scanning to determine the staging of
tumor-induced osteomalacia has also been described. In 1 reported
case, a knee tumor that was responsible for producing TIO was
detected by whole-body Tl-201 and (metaiodobenzylguanidine) Tc-99m
scintigraphy.8 Recently, whole-body Tc-99m
methoxyisobutyl-isonitrile (MIBI) scanning has been described as a
part of simplified protocol that is cost- and time-effective. The
authors recommended that whole-body MRI scans should be reserved
only for patients with Tc-99m MIBI-negative scans.9
Many of these tumors express somatostatin receptors that
regulate secretory activity, as has been shown by other similar
neuroendocrine tumors. Octreotide-labeled In-111 scanning has been
successfully used for the detection of such tumors,10 as
is also seen in the present case. On the basis of an octreotide
scan, TIO can be classified as OctreoScan-positive tumors or
OctreoScan-negative tumors. This classification also has bearing on
the treatment. OctreoScan-negative tumors should be further
evaluated by cost- effective nuclear scans followed by limited MRI.
The role of -fluorodeoxyglucose positron emission tomography
(PET)/CT imaging is well established in the detection of various
tumors, and its role in TIO is now being defined, with encouraging
results. However, PET scans usually do not include the limbs. It is
mandatory to include the limbs in the field, as these tumors are
common in the limbs and may be easily missed.
Unexplained generalized bone pain or multiple fractures must be
tested for calcium and phosphate homeostasis for a complete
diagnostic work-up. Detection of renal phosphate wasting indicates
the need for further evaluation for possible hereditary and
On the basis of the OctreoScan results, cases of TIO should be
classified as either OctreoScan-positive tumors or
OctreoScan-negative tumors. This classification also has a bearing
on the treatment. OctreoScan-negative tumors should be further
evaluated with cost-effective nuclear scans. Once the tumor is
detected, limited MRI should be performed. For PET scan evaluation,
it is mandatory to include the limbs in the field (a vertex-to-toes
protocol), as these tumors are common in the limbs and may easily
be missed if the limbs are truncated.
- Fanconi A, Fischer JA, Prader A. Serum parathyroid hormone
concentrations in hypophosphatemic vitamin D resistant rickets.
Helv Paediatr Act. 1974;29:187-194.
- McCance RA. Osteomalacia with Looser's nodes (Milkman's
syndrome) due to a raised resistance to vitamin D acquired about
the age of 15 years. Q J Med. 1947;16:33-
- Prader A, Illing R, Uehlinger E, Stalder G. Rickets following
bone tumor. Rachitis infolge knochentumors. [In German.] Helv
Paediatr Acta. 1959;14:554-565.
- Econs MJ, Drezner MK. Tumor-induced osteomalacia-unveiling a
new hormone. New Eng J Med. 1994;330:1679-1681.
- Gonzalez-Compta X, Manos-Pujol M, Folia-Fernandez M, et al.
Oncogenic osteomalacia: Case report and review of head and neck
associated tumors. J Laryngol Otol. 1998;112:389-392.
- Weidner N, Santa Cruz D. Phosphaturic mesenchymal tumors. A
polymorphous group causing osteomalacia or rickets. Cancer.
- Folpe AL, Fanburg-Smith JC, Billings SD, et al. Most
osteomalacia-associated mesenchymal tumors are a single
histopathologic entity: An analysis of 32 cases and a comprehensive
review of the literature. Am J Surg Path. 2004;28:1-30.
- Kimizuka T, Ozaki Y, Sumi Y. Usefulness of 201Tl and 99mTc MIBI
scintigraphy in a case of oncogenic osteomalacia. Ann Nucl Med.
- Gambhir S, Kongara S, Pawaskar A, et al. Simplified protocol
for detection and localization of tumor causing adult onset
sporadic hypophosphatemic osteomalacia. Abstract No.1039. J Nuc
Med. 2005;46(2 Abstract Book):317-318.
- Rhee Y, Lee JD, Shin KH et al. Oncogenic osteomalacia
associated with mesenchymal tumor detected by indium-111 octreotide
scientigraphy. Clin Endocrinol (Oxf). 2001;54:551-554.