Tumor localization and biochemical response to cure in tumor-induced osteomalacia

Abstract

Tumor-induced osteomalacia (TIO) is a rare disorder of phosphate wasting due to fibroblast growth factor-23 (FGF23)-secreting tumors that are often difficult to locate. We present a systematic approach to tumor localization and postoperative biochemical changes in 31 subjects with TIO. All had failed either initial localization, or relocalization (in case of recurrence or metastases) at outside institutions. Functional imaging with ¹¹¹Indium-octreotide with single photon emission computed tomography (octreo-SPECT or SPECT/CT), and ¹⁸fluorodeoxyglucose positron emission tomography/CT (FDG-PET/CT) were performed, followed by anatomic imaging (CT, MRI). Selective venous sampling (VS) was performed when multiple suspicious lesions were identified or high surgical risk was a concern. Tumors were localized in 20 of 31 subjects (64.5%). Nineteen of 20 subjects underwent octreo-SPECT imaging, and 16 of 20 FDG-PET/CT imaging. Eighteen of 19 (95%) were positive on octreo-SPECT, and 14 of 16 (88%) on FDG-PET/CT. Twelve of 20 subjects underwent VS; 10 of 12 (83%) were positive. Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were as follows: sensitivity = 0.95, specificity = 0.64, PPV = 0.82, and NPV = 0.88 for octreo-SPECT; sensitivity = 0.88, specificity = 0.36, PPV = 0.62, and NPV = 0.50 for FDG-PET/CT. Fifteen subjects had their tumor resected at our institution, and were disease-free at last follow-up. Serum phosphorus returned to normal in all subjects within 1 to 5 days. In 10 subjects who were followed for at least 7 days postoperatively, intact FGF23 (iFGF23) decreased to near undetectable within hours and returned to the normal range within 5 days. C-terminal FGF23 (cFGF23) decreased immediately but remained elevated, yielding a markedly elevated cFGF23/iFGF23 ratio. Serum 1,25-dihydroxyvitamin D₃ (1,25D) rose and exceeded the normal range. In this systematic approach to tumor localization in TIO, octreo-SPECT was more sensitive and specific, but in many cases FDG-PET/CT was complementary. VS can discriminate between multiple suspicious lesions and increase certainty prior to surgery. Sustained elevations in cFGF23 and 1,25D were observed, suggesting novel regulation of FGF23 processing and 1,25D generation.

Figure 1

Anatomical location of the 20 localized tumors confirmed to be causing tumor-induced osteomalacia. Black X’s represent tumors located in soft tissues (10/20, 50%); white X’s represent tumors located in bone (10/20, 50%). Star-like structures represents metastases. Four tumors occurred in the head and neck, 14 occurred in the extremities, and 2 occurred in the torso. Two subjects had metastases, both of which occurred in the lungs. One originated in the left forearm and the other arose from the right mandible. Fourteen of the 20 tumors were found on the left side of the body, 5 were found on the right side, and one was midline.

Figure 2

Mineral metabolism after tumor resection: Levels of various measures of mineral metabolism were determined in ten subjects for up to 11 days after tumor resection. Blood was drawn at 8 am after an overnight fast. The mean serum phosphorus was normal by day 5 and in all subjects it was normal by day 7 (A). Plasma iFGF23 decreased rapidly after tumor resection, but did not return to normal in all subjects until day 11 (B). Plasma cFGF23 declined (but not into the normal range) and remained elevated post-operatively (C). As a consequence, the cFGF23/iFGF23 ratio was markedly increased and remained elevated throughout the period of monitoring (D). 1,25-dihydroxyvitamin D₃ began to rise immediately postoperatively, and was significantly elevated above the normal range during most of the postoperative period (E). Average PTH levels were elevated for the first several days following surgery then normalized (F). The elevation in the average PTH values were driven by very high levels in one subject (number 28) who was eventually found to have tertiary hyperparathyroidism and whose PTH values were quite elevated (at baseline 400-600 pg/ml). The PTH values in all other subjects were normal. Mean blood calcium levels were normal throughout the observation period (G). The normal ranges are indicated by the boxed areas.

Figure 2

Mineral metabolism after tumor resection: Levels of various measures of mineral metabolism were determined in ten subjects for up to 11 days after tumor resection. Blood was drawn at 8 am after an overnight fast. The mean serum phosphorus was normal by day 5 and in all subjects it was normal by day 7 (A). Plasma iFGF23 decreased rapidly after tumor resection, but did not return to normal in all subjects until day 11 (B). Plasma cFGF23 declined (but not into the normal range) and remained elevated post-operatively (C). As a consequence, the cFGF23/iFGF23 ratio was markedly increased and remained elevated throughout the period of monitoring (D). 1,25-dihydroxyvitamin D₃ began to rise immediately postoperatively, and was significantly elevated above the normal range during most of the postoperative period (E). Average PTH levels were elevated for the first several days following surgery then normalized (F). The elevation in the average PTH values were driven by very high levels in one subject (number 28) who was eventually found to have tertiary hyperparathyroidism and whose PTH values were quite elevated (at baseline 400-600 pg/ml). The PTH values in all other subjects were normal. Mean blood calcium levels were normal throughout the observation period (G). The normal ranges are indicated by the boxed areas.

Figure 3

An example of a case illustrating octreo-SPECT/CT and FDG-PET/CT complementarity: A 15-year-old girl who was found to have tumor-induced osteomalacia had an FDG-PET/CT study that demonstrated many areas of physiologic (e.g., brain, heart, kidneys) and non-physiologic (e.g., arrows) uptake (A). Subsequently an octreo-SPECT/CT study was performed that initially was read as negative (B). Guided by the non-physiologic FDG-PET/CT findings, a reevaluation of the octreo-SPECT/CT identified a suspicious lesion on the lateral aspect of the proximal right tibia on SPECT (C) and fused SPECT/CT (D) images (arrows). In retrospect the lesion was evident on the whole body image (B, arrow). Anatomic imaging identified a tumor on MRI (E). Further confirmation was deemed necessary prior to surgical resection, so venous sampling (VS) was performed. VS revealed a clear step-up in the region of the tumor suggested by functional and anatomical imaging (F&G). In panel F, the values indicate the intact FGF23 concentration at the location indicated by the arrows. In panel G, values from sites sampled are shown. The peripheral value was 188 pg/ml and the values at sites adjacent to the lesion were 1320 and 1535 pg/ml. The lesion was resected and the subject was cured.

Figure 3

An example of a case illustrating octreo-SPECT/CT and FDG-PET/CT complementarity: A 15-year-old girl who was found to have tumor-induced osteomalacia had an FDG-PET/CT study that demonstrated many areas of physiologic (e.g., brain, heart, kidneys) and non-physiologic (e.g., arrows) uptake (A). Subsequently an octreo-SPECT/CT study was performed that initially was read as negative (B). Guided by the non-physiologic FDG-PET/CT findings, a reevaluation of the octreo-SPECT/CT identified a suspicious lesion on the lateral aspect of the proximal right tibia on SPECT (C) and fused SPECT/CT (D) images (arrows). In retrospect the lesion was evident on the whole body image (B, arrow). Anatomic imaging identified a tumor on MRI (E). Further confirmation was deemed necessary prior to surgical resection, so venous sampling (VS) was performed. VS revealed a clear step-up in the region of the tumor suggested by functional and anatomical imaging (F&G). In panel F, the values indicate the intact FGF23 concentration at the location indicated by the arrows. In panel G, values from sites sampled are shown. The peripheral value was 188 pg/ml and the values at sites adjacent to the lesion were 1320 and 1535 pg/ml. The lesion was resected and the subject was cured.

Figure 4

An example of venous sampling in discriminating between two potential sites of tumor. Whole body octreo-SPECT was performed and identifed two suspicious lesions, white arrows (A). FDG-PET/CT suggested multiple lesions, including the lesion in the foot (B). The white asterisk (B) indicates the injection site. Anatomincal imaging studies confirmed the presence of a lesion at the brain-bone interface on CT scan (C), as well as a lesion on the plantar surface as shown on 3D CT scan (D). Venous sampling at these two sites was performed (E& F). In panels E & F, the course of the catheter the tips are indicated by white arrow heads. Measurement of intact FGF23 levels clearly revealed that the lesion in the foot was the source of the FGF23 (G).

Figure 4

An example of venous sampling in discriminating between two potential sites of tumor. Whole body octreo-SPECT was performed and identifed two suspicious lesions, white arrows (A). FDG-PET/CT suggested multiple lesions, including the lesion in the foot (B). The white asterisk (B) indicates the injection site. Anatomincal imaging studies confirmed the presence of a lesion at the brain-bone interface on CT scan (C), as well as a lesion on the plantar surface as shown on 3D CT scan (D). Venous sampling at these two sites was performed (E& F). In panels E & F, the course of the catheter the tips are indicated by white arrow heads. Measurement of intact FGF23 levels clearly revealed that the lesion in the foot was the source of the FGF23 (G).

Figure 5

Alogorithm for systematic approach to localizing tumors in tumor-induced osteomalacia. After confirming a clinical and biochemical picture of tumor-induced osteomalacia, we recommend obtaining functional imaging as a first step in tumor localization. Octreo-SPECT (SPECT/CT if available) is the recommended initial screening imaging test, as it was shown to have greater specificity and sensitivity than FDG-PET/CT. If a single lesion suspcious for TIO is found and it is confirmed on anatomical imaing and carries a reasonable surgical morbidity, surgical resection is recommended. If multiple lesions or no lesions are found on octreo-SPECT, FDG-PET/CT should follow. This may help to identify a lesion that was not initially seen on octreo-SPECT (as in Fig. 3), or help to confirm a lesion seen on octreo-SPECT. If appropriate, proceed to anatomical imaging with CT and/or MRI. If the area with the suspected lesion entails high surgical morbidity, or if multiple lesions are identified, selective venous sampling is recommended to confirm or rule out the tumor. If no lesion is found or a suspected lesion(s) is not confirmed on venous sampling, medical therapy is recommended.