Oncogenic Osteomalacia: Exact Tumor Localization by Co-Registration of Positron Emission and Computed Tomography

Authors


  • The authors state that they have no conflicts of interest.

Abstract

In oncogenic osteomalacia, the causative tumor is almost always difficult to find. A novel diagnostic approach is presented that facilitates a precise and rapid localization of the associated lesion by PET-CT co-registration using the radiotracer 68Ga-DOTANOC.

In oncogenic osteomalacia, the causative tumor is almost always difficult to find. A novel diagnostic approach is presented that facilitates a precise and rapid localization of the associated lesion by PET-CT co-registration using the radiotracer 68Ga-DOTANOC.

Introduction: Oncogenic osteomalacia (OOM) is an uncommon disorder characterized by hyperphosphaturia, hypophosphatemia, decreased vitamin D3 serum levels, and osteomalacia. The paraneoplastic syndrome is exclusively driven by a small somatostatin receptor (sst)-positive tumor that produces phosphatonins, proteins that cause renal phosphate loss. OOM can be cured completely on tumor removal. However, the exact tumor localization is the most challenging step, because the lesion is notoriously difficult to detect by common imaging techniques.

Materials and Methods: A 60-year-old woman complained of severe pain in her back and chest wall, muscle weakness, and reduced physical activity for >1 year. She suffered a metatarsal fracture and presented with hyperphosphaturia and hypophosphatemia. OOM was suspected, and a meticulous search for the tumor was initiated by conventional imaging techniques, sst-mediated imaging using 111In-octreotide scintigraphy, and 68Ga-DOTANOC-based positron emission tomography (PET)-CT co-registration. 68Ga-DOTANOC is a novel radiopharmaceutical compound in which the somatostatin analog octreotide is modified at position 3, chelated with DOTA, and complexed with 68Gallium. 68Ga-DOTANOC has an improved affinity to sst2 and sst5 relative to other radiopeptides.

Results: Whereas common imaging techniques such as CT failed to localize the tumor, 111In-octreotide scintigraphy was able to detect the lesion, but only PET-CT using 68Ga-DOTANOC revealed the exact tumor localization in the right femoral head. On tumor resection, the well being of the patient improved significantly, and biochemical parameters returned to normal.

Conclusions: 68Ga-DOTANOC-based PET-CT is a novel and powerful approach to detect sst-positive tumors in a timely manner and to provide highly resolved images facilitating the development of a therapeutic strategy.

INTRODUCTION

Oncogenic osteomalacia (OOM) is a rare paraneoplastic syndrome predominantly caused by a small benign mesenchymal tumor that can be hidden in obscure anatomical locations. Hyperphosphaturia caused by an increased renal phosphate clearance and subsequent hypophosphatemia together with a reduced vitamin D3 serum concentration, and osteomalacia, are the key findings. The disease-related metabolic disturbances are thought to be exclusively driven by tumor-produced proteins such as fibroblast growth factor 23 (FGF23), secreted frizzled related protein 4 (sFRP4), matrix extracellular phosphoglycoprotein (MEPE), and FGF7, which are reported to exert a regulatory influence either independently or cooperatively on phosphate homeostasis by distinct mechanisms and are therefore collectively considered as phosphatonins.(1)

Localizing the causative tumor is most crucial to the patient because, to date, only its complete surgical removal fully cures the disease. Unfortunately, commonly used imaging techniques such as CT or MRI frequently fail to detect the tumor.

Tumors associated with OOM express a variable pattern of the five somatostatin receptors (sst1–sst5), which have been used for sst-based molecular imaging by 111In-octreotide or 111In-pentetreotide scintigraphy.(2–8) However, scintigraphy alone is not capable of providing either a precise anatomical localization of the lesion or highly resolved images. Thus, additional imaging is necessary to perform the required surgical procedure.

Alternatively, a more straightforward detection and exact localization of the related tumor can be achieved by co-registration of positron emission tomography (PET) and CT. PET-CT alone can generally overcome all of these technical shortcomings, especially if a radioligand is used that targets a broader range of sst-positive tumors because of improved receptor binding properties, for example, the novel radioligand 68Ga-DOTANOC.(9)

In this novel radiopharmaceutical compound, the amino acid phenylalanine in position 3 of the octapeptide octreotide is replaced by naphthylalanine. Octreotide itself is coupled to the macrocyclic chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), leading to the DOTA-conjugated peptide (DOTANOC [DOTA0-D-Phe1-1-Nal3]-octreotide), which in turn is chelated with 68Gallium (68Ga), giving rise to 68Ga-DOTANOC.(10) The binding of the positron emitter 68Ga to the peptide ligand enables the tumor to be located by PET scanning.

This is the first report of OOM in which the tumor has been exactly localized by co-registration of PET and CT using the radiopharmaceutical compound 68Ga-DOTANOC.

CASE SUMMARY

A 60-year-old woman complained of severe pain predominantly in the lower back and chest wall for >1 year before presentation at our hospital. The symptoms were accompanied by muscle weakness and reduced physical activity that worsened over time and on exercising. Both her past medical history and her family history were without evidence of bone or rheumatic disease or malignancy. The clinical examination was unremarkable. X-ray of the chest, spine, and pelvis revealed mild degeneration, which was treated elsewhere by acupuncture and nonsteroidal analgesic drugs without any significant relief of symptoms. Six months later, she suffered a stress fracture of the right second metatarsal.

Blood biochemistry disclosed a hypophosphatemia with a serum phosphate concentration of 0.53 mM (reference range: 0.83–1.67 mM), elevated levels of PTH (81.6 pg/ml; reference range: 6–40 pg/ml), alkaline phosphatase (216 U/liter; reference range: 35–110 U/liter), and bone-specific alkaline phosphatase (149 U/liter; reference range: <60 U/liter). Other parameters examined, such as serum calcium, vitamin D3, calcitonin, serum creatinine, and creatinine clearance, were within the physiological range. The renal tubular maximum for the reabsorption of phosphate normalized to the glomerular filtration rate (TmP/GFR) was determined by the method of Walton and Bijvoet(11) and found to be reduced (0.4 mM; reference range: 0.8–1.4 mM). Additional laboratory analyses revealed no abnormalities of the peripheral blood cell count, thyroid hormones, serum protein electrophoresis, tumor markers, or liver function. However, a hyperlipidemia type IIa was diagnosed.

Despite exogenous administration of phosphate (Reducto spezial; 613 mg, three times per day) and calcitriol (Rocaltrol; 0.25 μg/day), serum phosphate concentrations did not return to normal, and clinical symptoms persisted.

Whole body Tc-99m-MDP scintigraphy with single photon emission CT (SPECT) revealed multiple disseminated foci distributed throughout the entire skeleton, probably caused by increased metabolic activity because of fracture healing or by other fracture-independent causes. Bone densitometry by DXA documented a modestly decreased BMD in both the left femoral neck (BMD: 0.798 g/cm2; T score: −1.52; Z score: −0.34) and lumbar spine L1–L4 (BMD: 0.955 g/cm2; T score: −1.87: Z score: −0.59).

Based on these initial findings, the diagnosis of an acquired hypophosphatemic vitamin D–resistant osteomalacia was made, which was supported by a histological analysis of a bone biopsy sample. Given the late onset of the disease in advanced adulthood, inherited phosphate wasting syndromes leading to hyperphosphaturia, hypophosphatemia, and ultimately osteomalacia, such as the autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemic rickets (XLH), or the inherited forms of Fanconi syndrome, were diagnostically excluded. In addition, the acquired and idiopathic forms of Fanconi syndrome, which may appear at any age, mostly because of exposure to noxious agents, were also excluded based on a unremarkable clinical history, including the absence of any indications in previous medication history and also because of the absence of excessive renal loss of characteristic substances such as amino acids, proteins, glucose, potassium, or bicarbonate. Fibrous dysplasia of bone, also known as Jaffe-Lichtenstein syndrome, is a genetic, noninherited, benign disease characterized by a proliferation of fibro-osseous tissue that can affect virtually any bone in a monostotic or polyostotic fashion and can present along with endocrine and cutaneous abnormalities (McCune-Albright syndrome). It has been reported to be associated with hyperphosphaturia and osteomalacia caused by elevated levels of FGF23.(12) However, this disease was also ruled out given the lack of distinctive skeletal lesions on X-ray and bone scan and the advanced age of the patient. Thus, tumor-induced OOM seemed to be the most likely diagnosis.

In treating this disease, the exact tumor localization is very important but not easy to achieve. Frequently, conventional imaging techniques are insufficient to detect the tumor.(3,13,14) To track down the suspected causative tumor, we performed somatostatin receptor (sst) whole body imaging using 150 MBq 111Indium- (111In) octreotide, which revealed a high radiotracer uptake in the right groin region.

However, scintigraphy alone is incapable of providing images with the resolution required to precisely localize the tumor and to perform the surgical treatment. Detection and exact localization of the lesion in the subchondral ventral portion of the right femoral head was ultimately achieved by PET-CT co-registration using the somatostatin receptor radioligand 68Ga-DOTANOC.

Briefly, imaging was performed using a dedicated full-ring PET-CT scanner (Biograph LSO DUO; Siemens, Erlangen, Germany) with a reconstructed image resolution of 6-mm full-width half-maximum (FWHM) and a 15-cm transaxial field of view combined with a two-slice CT (5-mm slice thickness) using the Siemens-Syngo software platform. Emission scans in a 3D acquisition mode were started 90 minutes after intravenous injection of 120 MBq 68Ga-DOTANOC into the right cubital vein. DOTANOC was kindly provided by H Maecke, University Hospital Basel, Basel, Switzerland, and labeled according to Meyer et al.(15) The whole body scan comprised 14 bed positions and lasted for 60 minutes. After CT-based attenuation correction and iterative reconstruction using a maximum-likelihood algorithm (OSEM, two iterations, eight subsets), standardized uptake values (SUVs) were calculated according to Zasadny and Wahl.(16) A pathological radionuclide accumulation was found in the right femoral head (SUV max: 10.8) (Fig. 1).

Figure Figure 1.

A pathological radiotracer uptake (SUV max: 10.8) was found in the ventral portion of the right femoral head by PET and CT co-registration on injection of 120 MBq 68Ga-DOTANOC. The lesion is indicated by arrows.

Subsequently, a standard total right hip arthroplasty was performed to remove the entire tumor, which histology revealed to be a cell-rich hemangiopericytoma-like mesenchymal tumor.

Within 2 days after surgery, the serum phosphate level returned to normal (1.52 mM; reference range: 0.83–1.67 mM), allowing the withdrawal of the oral phosphate supplementation. Normalization of both alkaline phosphatase (89 U/liter; reference range: 35–110 U/liter) and bone-specific alkaline phosphatase (46 U/liter; reference range: <60 U/liter) occurred within a few weeks, whereas the concentration of intact PTH slowly decreased but remained elevated (65.0 pg/ml; reference range: 6–40 pg/ml) for a longer period of time. After 2 months, the patient was fully mobile, with complete recovery of muscle strength and full weight-bearing capacity, and consequently, a significantly improved overall well being. At follow-up 7 months after tumor removal, BMD was increased to ˜11% in the femoral neck and ˜4% in the lumbar spine.

DISCUSSION

OOM is a rare syndrome caused by a paraneoplastic phenomenon leading to renal phosphate loss and subsequent hypophosphatemia, which seems to be exclusively driven by the neoplastic lesion and disappears completely after surgical resection of the tumor within a remarkably short period of time. It affects both sexes and all ages.(17) In most cases, the tumor itself is of mesenchymal origin, benign, slow growing, small in size, not clinically apparent, and extremely hard to find. Tumors associated with OOM have been reported to occur at many different locations without a discernible prevalence in location.(17–20) Thus, other than the recognition of the disease itself, detection of the tumor is by far the major challenge in the treatment of this disorder. Failure to discover the tumor may lead to a delayed diagnosis up to several years from the onset of symptoms.

Based on a histopathological survey, the majority of OOM is usually caused by an extremely rare phosphaturic mesenchymal tumor (mixed connective tissue variant; PMTMCT). However, other types such as hemangiopericytoma, osteosarcoma, and giant cell tumor have also been found.(21)

Severe hyperphosphaturia and subsequent hypophosphatemia are the key findings in addition to osteomalacia. Although the serum concentration of vitamin D3 is typically reduced, representing another hallmark in OOM, it has also been reported to be within the physiological range, as in this case.(6,13,14,17) However, in the context of hypophosphatemia and secondary hyperparathyroidism, a vitamin D3 serum level within the physiological range is relatively reduced with regard to the diminished serum phosphate concentration and therefore considered to be inappropriate.

The decreased renal phosphate reabsorption threshold TmP/GFR indicates a phosphate leakage, which is characteristic for OOM. Thus, hypophosphatemia is secondary to the impairment in renal proximal tubular phosphate reabsorption.

The underlying molecular mechanisms by which these tumors cause imbalances in phosphate homeostasis are not yet completely elucidated. However, according to the prevailing theory, several phosphate-regulating factors, the so-called phosphatonins, such as sFRP4, MEPE, FGF7, and FGF23, are produced by the tumor tissue and alter phosphate homeostasis by decreasing the renal sodium-dependent phosphate transport either independently or in a cooperative manner. FGF23 and sFRP4 have also been reported to inhibit the synthesis of vitamin D3, leading to a decreased intestinal phosphate absorption, in addition to the reduction in phosphate retention induced by phosphatonins generally. However, by either mechanism, the phosphatonins participate in mediating the pathophysiological effects related to OOM.(1)

In particular, FGF23 has been shown to play a central role in OOM,(22) and elevated FGF23 serum concentrations were found in many but not all patients with OOM.(23) Therefore, some authors suggest that FGF23 measurement has a value in diagnosing OOM,(13,14) although OOM is generally diagnosed in the context of clinical findings and biochemical parameters.

Attempts to identify somatostatin receptor–positive lesions in OOM by conventional imaging techniques such as CT or MRI frequently fail, but tumor detection has successfully been achieved by scintigraphy using the radioligands 111Indium- (111In) octreotide or 111In-pentetreotide.(2–8)

All of the five characterized human somatostatin receptors (sst1–sst5) have been shown alone or in various combinations on the surface of a broad variety of human tumor cells generally and on tumors associated with OOM specifically. However, the binding of the synthetic somatostatin analog octreotide is limited to subtypes sst1, sst3, and sst5. Therefore, only tumors that express the respective binding pattern of octreotide can be targeted, and small tumors are only detectable at a high receptor density.(24)

In 68Ga-DOTANOC, the octapeptide octreotide is modified at position 3, coupled to the macrocyclic chelator DOTA, and complexed with the positron emitter 68Gallium, giving rise to 68Ga-DOTANOC. The specific modification of octreotide in 68Ga-DOTANOC is located in the somatostatin receptor–interacting region, which leads to a higher affinity of 68Ga-DOTANOC to both sst2 and sst5 and improves the binding to somatostatin receptor–positive tumor tissues compared with other, more widely used standard radiopeptides such as 111In-DOTATOC, which only binds sst2.(9,10)

The use of 68Ga is that it is a positron emitter and thus enables PET scanning. 68Ga has a short half-life of 68 minutes and can conveniently be produced in a cyclotron-independent manner using a 68Ge/68Ga generator that has a long half-life of 270.8 days. Given the short half-life of 68Ga, the diagnostic time frame is limited to 2–3 h, which equals two to three physical half-lives.(15)

Recently, 111In-DOTATOC was successfully applied in a case of OOM.(25) However, DOTANOC is reported to be more sensitive because of its improved sst-binding properties and is therefore an excellent candidate for diagnosing sst-positive tumors.(9,10) This greater sensitivity is highly relevant for clinical applications because different tumors have a variable expression of different receptor subtypes, of which sst2 is reported to be the most widely occurring form.(26) Thus, a broader and improved binding profile is a prerequisite to extend the overall spectrum of tumors to which a compound can bind and to facilitate a multireceptor mediated tumor targeting in diagnosis and potentially in peptide receptor radionuclide therapy (PRRT).

PET imaging using DOTA-linked positron emitting moieties such as 111In, 68Ga, or 86Yttrium (86Y) generally allows for a higher spatial resolution compared with other techniques such as SPECT. Combined with CT, PET-CT perfectly correlates morphological information delineated by spiral CT and functional parameters provided by the pathological tumor-dependent tracer uptake, leading to a precise alignment of the lesion with its surrounding anatomical structures in a highly resolved manner.(27)

In addition to its improved ability to locate the tumor, DOTANOC may serve as a powerful tool in PRRT by targeting DOTA-coupled β-particle–emitting radionuclides such as 90Yttrium (90Y), 177Lutetium (177Lu), or the auger electron emitting 111Indium (111In) to sst-positive tumors, as has been reported for treating neuroendocrine lesions with other radiopeptides.(28,29)

In conclusion, oncogenic osteomalacia should be suspected in any patient who presents with metabolic bone disease associated with hypophosphatemia and hyperphosphaturia. Once suspected, a vigorous and meticulous search for a small, inconspicuous tumor should be initiated. We emphasize the value of PET-CT using 68Ga-DOTANOC in patients in which OOM is suspected as a very effective approach to exactly localize the causative tumor. This imaging technique is likely to be of great importance for an early diagnosis and for developing therapeutic strategies in OOM based on the highly resolved images and the precise anatomical co-relation it provides.

Acknowledgements

We thank WC Horne and T Carpenter for critical comments and careful review of the manuscript.

Ancillary