Pediatr Radiol DOI 10.1007/s00247-014-3029-6
CASE REPORT
False-positive In-111 DTPA octreotide scintigraphy in bilateral tibial insufficiency fracture Reza Vali & Marilyn Ranson & Elizabeth Harvey & Amer Shammas
Received: 5 December 2013 / Revised: 11 March 2014 / Accepted: 5 May 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract We present a case of bilateral tibial insufficiency fracture in which indium (In)-111 diethylenetriamine pentaacetic acid (DTPA) octreotide scan showed increased activity in the region of the fracture. The scan was performed in a 5-year-old girl with severe refractory hypertension and elevated plasma metanephrines for evaluation of possible neuroendocrine tumor. Octreotide scan is usually positive in neuroendocrine and some other tumors but also shows positive results in a number of other conditions. However insufficiency fracture has not been reported as a positive finding on octreotide scan in children. This may relate to the expression of somatostatin membrane receptor in activated white blood cells or expression of somatostatin receptors by bone cells. Keywords In-111 DTPA octreotide . Neuroendocrine tumors . Insufficiency fracture . Child
Introduction In-111 DTPA octreotide is a radiolabelled analogue of somatostatin that is commonly used to detect tumors with somatostatin receptors. These tumors include but are not limited to adrenal medullary tumors, functioning and non-functioning gastroenteropancreatic tumors, as well as some thyroid cancers and other tumors less common in the pediatric population (Table 1) [1]. Other disease conditions may show increased InR. Vali (*) : M. Ranson : A. Shammas Diagnostic Imaging Department, The Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto, Canada M5G 1X8 e-mail: [email protected] E. Harvey Pediatric Department (Nephrology), The Hospital for Sick Children, University of Toronto, Toronto, Canada
111 DTPA octreotide activity such as autoimmune diseases, notably Grave disease, bacterial pneumonia, cerebrovascular accident, granulomas and radiation pneumonitis (Table 1) [1]. This is a unique report of insufficiency fracture as a positive finding on In-111 DTPA octreotide scan in children. Case report A 5-year-old girl with severe refractory hypertension and elevated plasma metanephrine was referred for an In-111 DTPA octreotide scintigraphy for evaluation of possible neuroendocrine tumor such as pheochromocytoma. The girl had end-stage renal disease secondary to membrano-proliferative glomerulonephritis with intractable hypertension despite bilateral nephrectomy and initiation of dialysis, and she was relatively immobile for much of the time. There was no history of trauma. The laboratory examinations revealed a parathyroid hormone (PTH) level of 190 ng/L (normal: 16– 63 ng/L) within the target range for dialysis patients, and she had not experienced significant periods of severe secondary hyperparathyroidism. Her 25 hydroxy vitamin D level was in the normal range at 88 nmol/L (normal 7–250 nmol/L). A 1, 25 dihydroxy vitamin D level was not available. Following intravenous injection of 82 Mbq of In-111 octreotide, imaging was obtained in whole-body and spot views as well as single photon-emission computed tomography (SPECT) over the chest, abdomen and pelvis at 4 h, 24 h and 48 h. On octreotide scan, there was no definite focus of radiotracer activity to suggest a neuroendocrine tumor. However, there were two areas of increased activity at 24 h post radiotracer administration, one in the proximal left tibia and the other in the mid right tibia (Fig. 1). Delayed images at 48 h confirmed the presence of the abnormal activity. Because bone tumors, both benign and malignant, may have somatostatin receptors and show activity on octreotide scan, the girl was further evaluated with correlative radiography.
Pediatr Radiol Table 1 Tumoral and non-tumoral causes of In-111 DTPA octreotide uptake [1]
Tumors
Non-tumoral causes
DTPA diethylenetriamine pentaacetic acid
Adrenal medullary tumors Functioning gastroenteropancreatic (GEP) tumors Non-functioning GEP tumors Carcinoid tumors Medullary thyroid carcinoma Others
Autoimmune disease Recent surgery Bacterial pneumonia Cerebrovascular accident Fibrous dysplasia Granuloma Radiation pneumonitis
Pheochromocytoma, neuroblastoma, ganglioneuroma Gastrinoma, insulinoma, glucagonoma, vasoactive intestinal polypeptide secreting tumor
Paraganglioma, melanoma, Merkel cell tumor of the skin, small and non-small cell lung carcinomas, astrocytoma, meningioma, benign and malignant bone tumors, breast carcinoma, differentiated thyroid carcinoma, lymphoma, prostate cancer, medulloblastoma, primitive neuroectodermal tumor, renal cell carcinoma and sarcoma Rheumatoid arthritis, Grave disease, Grave ophthalmopathy
e.g., tuberculosis, sarcoid
On plain radiography there was a transverse band of sclerosis and periosteal new bone seen mainly in the medial aspect of the proximal left tibial shaft with similar but less marked sclerosis in the mid-shaft of the right tibia, suggesting the presence of insufficiency fracture (Fig. 2). On follow-up serial radiography performed 2 weeks and 4 weeks later there was further increased periosteal reaction related to the proximal left tibial diaphysis with a cortical lucency medially and an incomplete transverse fracture line, suggestive of a healing fracture. There was also interval development of periosteal reaction in the mid to distal right tibial diaphysis, also suggestive of an insufficiency fracture. Two months later there was progressive consolidated periosteal reaction along the lateral aspect of the proximal right tibial diaphysis, consistent with healing of the previously demonstrated fracture in this region (Fig. 3).
Discussion
Fig. 1 In-111 DTPA octreotide scan in a 5-year-old girl. No definite focus of abnormal activity was noted in the chest, abdomen and pelvis to suggest neuroendocrine tumor (not shown here). Two foci of increased activity are detected, one in the proximal left tibia and the other with less intensity in the mid right tibia
In-111 DTPA octreotide scan is a somatostatin analog that binds to somatostatin receptors on cell surfaces, predominantly somatostatin receptor subtypes 2 and 5, and it is generally regarded as a useful imaging modality for detection and staging of neuroendocrine tumors. Image acquisition is usually done 24 h after the intravenous injection of 3 Mbq/kg of In-111 octreotide [1]. Early imaging at 4 h before any bowel excretion of the radiotracer or delayed imaging at 48 h to allow clearance of the activity from the gut may also be done. SPECT imaging is usually necessary to detect small lesions in the chest and abdomen. Normally the activity can be seen in
Pediatr Radiol
Fig. 2 Anterior leg radiograph in the 5-year-old girl shows an area of sclerosis and periosteal reaction in the proximal left tibia (small arrow). The sclerosis is less prominent in the mid-shaft of the right tibia (long arrow)
the pituitary, thyroid, liver, spleen, kidneys, bladder, bowel and sometimes gallbladder [1]. The octreotide scan is mainly used for detection, localization, staging and follow-up of neuroendocrine tumors. It is, however, important to know that there are other tumors and disease conditions in which the octreotide scan may show abnormal activity (Table 1). In the majority of these conditions, either the tumor has a somatostatin receptor, or migration of inflammatory cells with positive somatostatin receptors is responsible for increased activity at the site of the lesion [2]. Insufficiency fractures occur when normal activity stresses a bone that is deficient in mineral or elastic resistance. The pathogenesis involves accelerated bone remodelling and probably capillary micro damage, which can lead to fluid leakage and migration of neutrophils and macrophages. Underlying abnormal bone conditions such as reduced bone density or hormonal imbalance are sometimes predisposing conditions. In our case, renal failure and prolonged immobilization from a very long hospitalization as well as elevated serum parathyroid hormone (PTH) level and osteopenia were considered to be the predisposing factors. Although the sensitivity of plain film to detect insufficiency fracture is relatively low, radiographic findings including periosteal new bone formation and endosteal thickening or a radiolucent line or a band of
Fig. 3 Two-month follow-up of anterior leg radiograph in the 5-year-old girl. Progression of consolidated periosteal reaction along the medial aspect of the proximal left tibial diaphysis is consistent with healing of the previously demonstrated fracture in this region (small arrow). A similar but less marked sclerosis in the mid-shaft of the right tibia is suggestive of insufficiency fracture (long arrow)
sclerosis are sufficient for the diagnosis in an appropriate clinical setting. Serial radiography is helpful for accurate diagnosis and evaluation of the healing process [3]. Reports of In-111 DTPA octreotide activity in insufficiency fracture in children are rare. The exact mechanism and the significance of octreotide activity in insufficiency fracture are unclear. A possible mechanism of octreotide activity is the migration of activated white blood cells and macrophages to the site of injury or adjacent soft tissue. Normal as well as activated lymphocytes, monocytes and macrophages have been shown to express somatostatin receptors [4]. Microdamage to blood vessels in insufficiency fracture allows fluid to leak into the surrounding tissue and is also associated with neutrophil and macrophage proliferation [5]. Increased activity can also be caused by increased delivery of the radiopharmaceutical to these areas secondary to inflammation. It is possible that somatostatin receptors are expressed by the osteocytes themselves. Neonatal rat bones have been shown to have somatostatin receptors in their osteoblastic precursors [6], probably responsible for regulating bone development. Reports of octreotide activity in both benign and
Pediatr Radiol
malignant bone tumors [7], which can be decreased after a course of cold (non-radioactive) octreotide therapy, also support the presence of specific somatostatin receptors in these lesions [8]. If there are somatostatin receptors in insufficiency fractures as suggested by octreotide scan in our patient, there may be a role for somatostatin in the pathogenesis or treatment of this condition [8]. Regardless of the underlying pathophysiology, it is essential to be aware of insufficiency fracture as a cause of In-111 DTPA octreotide activity in order to avoid unnecessary investigation or treatment. Conflicts of interest None
References 1. Balon HR, Goldsmith SJ, Siegel BA et al (2001) Procedure guideline for somatostatin receptor scintigraphy with (111) In-pentetreotide. J Nucl Med 42:1134–1138
2. Elliott DE, Li J, Blum AM et al (1999) SSTR2A is the dominant somatostatin receptor subtype expressed by inflammatory cells, is widely expressed and directly regulates T cell IFN-gamma release. Eur J Immunol 29:2454–2463 3. Papadimitriou NG, Christophorides J, Papadimitriou A et al (2007) Stress fractures in children: a review of 37 cases. Eur J Orthop Surg Traumatol 17:131–137 4. Van Hagen PM, Ligtenauer-Kaligig EG, Lambert SW et al (1997) Somatostatin receptor expression in clinical immunology. Immunol Letter 56:286 5. Romani WA, Gieck JH, Perrin DH et al (2002) Mechanisms and management of stress fractures in physically active persons. J Athl Train 37:306–314 6. Mackie EJ, Trechsel U, Bruns C (1990) Somatostatin receptors are restricted to a subpopulation of osteoblast-like cells during endochondral bone formation. Development 110:1233– 1239 7. Inanir S, Unlu M, Okudan B et al (1996) Indium-111 octreotide scintigraphy in patients with bone tumours of the extremities. Eur J Nucl Med 23:987–990 8. Chen CC, Czerwiec FS, Feuillan PP (1998) Visualization of fibrous dysplasia during somatostatin receptor scintigraphy. J Nucl Med 39: 238–240
CASE REPORT
False-positive In-111 DTPA octreotide scintigraphy in bilateral tibial insufficiency fracture Reza Vali & Marilyn Ranson & Elizabeth Harvey & Amer Shammas
Received: 5 December 2013 / Revised: 11 March 2014 / Accepted: 5 May 2014 # Springer-Verlag Berlin Heidelberg 2014
Abstract We present a case of bilateral tibial insufficiency fracture in which indium (In)-111 diethylenetriamine pentaacetic acid (DTPA) octreotide scan showed increased activity in the region of the fracture. The scan was performed in a 5-year-old girl with severe refractory hypertension and elevated plasma metanephrines for evaluation of possible neuroendocrine tumor. Octreotide scan is usually positive in neuroendocrine and some other tumors but also shows positive results in a number of other conditions. However insufficiency fracture has not been reported as a positive finding on octreotide scan in children. This may relate to the expression of somatostatin membrane receptor in activated white blood cells or expression of somatostatin receptors by bone cells. Keywords In-111 DTPA octreotide . Neuroendocrine tumors . Insufficiency fracture . Child
Introduction In-111 DTPA octreotide is a radiolabelled analogue of somatostatin that is commonly used to detect tumors with somatostatin receptors. These tumors include but are not limited to adrenal medullary tumors, functioning and non-functioning gastroenteropancreatic tumors, as well as some thyroid cancers and other tumors less common in the pediatric population (Table 1) [1]. Other disease conditions may show increased InR. Vali (*) : M. Ranson : A. Shammas Diagnostic Imaging Department, The Hospital for Sick Children, University of Toronto, 555 University Ave., Toronto, Canada M5G 1X8 e-mail: [email protected] E. Harvey Pediatric Department (Nephrology), The Hospital for Sick Children, University of Toronto, Toronto, Canada
111 DTPA octreotide activity such as autoimmune diseases, notably Grave disease, bacterial pneumonia, cerebrovascular accident, granulomas and radiation pneumonitis (Table 1) [1]. This is a unique report of insufficiency fracture as a positive finding on In-111 DTPA octreotide scan in children. Case report A 5-year-old girl with severe refractory hypertension and elevated plasma metanephrine was referred for an In-111 DTPA octreotide scintigraphy for evaluation of possible neuroendocrine tumor such as pheochromocytoma. The girl had end-stage renal disease secondary to membrano-proliferative glomerulonephritis with intractable hypertension despite bilateral nephrectomy and initiation of dialysis, and she was relatively immobile for much of the time. There was no history of trauma. The laboratory examinations revealed a parathyroid hormone (PTH) level of 190 ng/L (normal: 16– 63 ng/L) within the target range for dialysis patients, and she had not experienced significant periods of severe secondary hyperparathyroidism. Her 25 hydroxy vitamin D level was in the normal range at 88 nmol/L (normal 7–250 nmol/L). A 1, 25 dihydroxy vitamin D level was not available. Following intravenous injection of 82 Mbq of In-111 octreotide, imaging was obtained in whole-body and spot views as well as single photon-emission computed tomography (SPECT) over the chest, abdomen and pelvis at 4 h, 24 h and 48 h. On octreotide scan, there was no definite focus of radiotracer activity to suggest a neuroendocrine tumor. However, there were two areas of increased activity at 24 h post radiotracer administration, one in the proximal left tibia and the other in the mid right tibia (Fig. 1). Delayed images at 48 h confirmed the presence of the abnormal activity. Because bone tumors, both benign and malignant, may have somatostatin receptors and show activity on octreotide scan, the girl was further evaluated with correlative radiography.
Pediatr Radiol Table 1 Tumoral and non-tumoral causes of In-111 DTPA octreotide uptake [1]
Tumors
Non-tumoral causes
DTPA diethylenetriamine pentaacetic acid
Adrenal medullary tumors Functioning gastroenteropancreatic (GEP) tumors Non-functioning GEP tumors Carcinoid tumors Medullary thyroid carcinoma Others
Autoimmune disease Recent surgery Bacterial pneumonia Cerebrovascular accident Fibrous dysplasia Granuloma Radiation pneumonitis
Pheochromocytoma, neuroblastoma, ganglioneuroma Gastrinoma, insulinoma, glucagonoma, vasoactive intestinal polypeptide secreting tumor
Paraganglioma, melanoma, Merkel cell tumor of the skin, small and non-small cell lung carcinomas, astrocytoma, meningioma, benign and malignant bone tumors, breast carcinoma, differentiated thyroid carcinoma, lymphoma, prostate cancer, medulloblastoma, primitive neuroectodermal tumor, renal cell carcinoma and sarcoma Rheumatoid arthritis, Grave disease, Grave ophthalmopathy
e.g., tuberculosis, sarcoid
On plain radiography there was a transverse band of sclerosis and periosteal new bone seen mainly in the medial aspect of the proximal left tibial shaft with similar but less marked sclerosis in the mid-shaft of the right tibia, suggesting the presence of insufficiency fracture (Fig. 2). On follow-up serial radiography performed 2 weeks and 4 weeks later there was further increased periosteal reaction related to the proximal left tibial diaphysis with a cortical lucency medially and an incomplete transverse fracture line, suggestive of a healing fracture. There was also interval development of periosteal reaction in the mid to distal right tibial diaphysis, also suggestive of an insufficiency fracture. Two months later there was progressive consolidated periosteal reaction along the lateral aspect of the proximal right tibial diaphysis, consistent with healing of the previously demonstrated fracture in this region (Fig. 3).
Discussion
Fig. 1 In-111 DTPA octreotide scan in a 5-year-old girl. No definite focus of abnormal activity was noted in the chest, abdomen and pelvis to suggest neuroendocrine tumor (not shown here). Two foci of increased activity are detected, one in the proximal left tibia and the other with less intensity in the mid right tibia
In-111 DTPA octreotide scan is a somatostatin analog that binds to somatostatin receptors on cell surfaces, predominantly somatostatin receptor subtypes 2 and 5, and it is generally regarded as a useful imaging modality for detection and staging of neuroendocrine tumors. Image acquisition is usually done 24 h after the intravenous injection of 3 Mbq/kg of In-111 octreotide [1]. Early imaging at 4 h before any bowel excretion of the radiotracer or delayed imaging at 48 h to allow clearance of the activity from the gut may also be done. SPECT imaging is usually necessary to detect small lesions in the chest and abdomen. Normally the activity can be seen in
Pediatr Radiol
Fig. 2 Anterior leg radiograph in the 5-year-old girl shows an area of sclerosis and periosteal reaction in the proximal left tibia (small arrow). The sclerosis is less prominent in the mid-shaft of the right tibia (long arrow)
the pituitary, thyroid, liver, spleen, kidneys, bladder, bowel and sometimes gallbladder [1]. The octreotide scan is mainly used for detection, localization, staging and follow-up of neuroendocrine tumors. It is, however, important to know that there are other tumors and disease conditions in which the octreotide scan may show abnormal activity (Table 1). In the majority of these conditions, either the tumor has a somatostatin receptor, or migration of inflammatory cells with positive somatostatin receptors is responsible for increased activity at the site of the lesion [2]. Insufficiency fractures occur when normal activity stresses a bone that is deficient in mineral or elastic resistance. The pathogenesis involves accelerated bone remodelling and probably capillary micro damage, which can lead to fluid leakage and migration of neutrophils and macrophages. Underlying abnormal bone conditions such as reduced bone density or hormonal imbalance are sometimes predisposing conditions. In our case, renal failure and prolonged immobilization from a very long hospitalization as well as elevated serum parathyroid hormone (PTH) level and osteopenia were considered to be the predisposing factors. Although the sensitivity of plain film to detect insufficiency fracture is relatively low, radiographic findings including periosteal new bone formation and endosteal thickening or a radiolucent line or a band of
Fig. 3 Two-month follow-up of anterior leg radiograph in the 5-year-old girl. Progression of consolidated periosteal reaction along the medial aspect of the proximal left tibial diaphysis is consistent with healing of the previously demonstrated fracture in this region (small arrow). A similar but less marked sclerosis in the mid-shaft of the right tibia is suggestive of insufficiency fracture (long arrow)
sclerosis are sufficient for the diagnosis in an appropriate clinical setting. Serial radiography is helpful for accurate diagnosis and evaluation of the healing process [3]. Reports of In-111 DTPA octreotide activity in insufficiency fracture in children are rare. The exact mechanism and the significance of octreotide activity in insufficiency fracture are unclear. A possible mechanism of octreotide activity is the migration of activated white blood cells and macrophages to the site of injury or adjacent soft tissue. Normal as well as activated lymphocytes, monocytes and macrophages have been shown to express somatostatin receptors [4]. Microdamage to blood vessels in insufficiency fracture allows fluid to leak into the surrounding tissue and is also associated with neutrophil and macrophage proliferation [5]. Increased activity can also be caused by increased delivery of the radiopharmaceutical to these areas secondary to inflammation. It is possible that somatostatin receptors are expressed by the osteocytes themselves. Neonatal rat bones have been shown to have somatostatin receptors in their osteoblastic precursors [6], probably responsible for regulating bone development. Reports of octreotide activity in both benign and
Pediatr Radiol
malignant bone tumors [7], which can be decreased after a course of cold (non-radioactive) octreotide therapy, also support the presence of specific somatostatin receptors in these lesions [8]. If there are somatostatin receptors in insufficiency fractures as suggested by octreotide scan in our patient, there may be a role for somatostatin in the pathogenesis or treatment of this condition [8]. Regardless of the underlying pathophysiology, it is essential to be aware of insufficiency fracture as a cause of In-111 DTPA octreotide activity in order to avoid unnecessary investigation or treatment. Conflicts of interest None
References 1. Balon HR, Goldsmith SJ, Siegel BA et al (2001) Procedure guideline for somatostatin receptor scintigraphy with (111) In-pentetreotide. J Nucl Med 42:1134–1138
2. Elliott DE, Li J, Blum AM et al (1999) SSTR2A is the dominant somatostatin receptor subtype expressed by inflammatory cells, is widely expressed and directly regulates T cell IFN-gamma release. Eur J Immunol 29:2454–2463 3. Papadimitriou NG, Christophorides J, Papadimitriou A et al (2007) Stress fractures in children: a review of 37 cases. Eur J Orthop Surg Traumatol 17:131–137 4. Van Hagen PM, Ligtenauer-Kaligig EG, Lambert SW et al (1997) Somatostatin receptor expression in clinical immunology. Immunol Letter 56:286 5. Romani WA, Gieck JH, Perrin DH et al (2002) Mechanisms and management of stress fractures in physically active persons. J Athl Train 37:306–314 6. Mackie EJ, Trechsel U, Bruns C (1990) Somatostatin receptors are restricted to a subpopulation of osteoblast-like cells during endochondral bone formation. Development 110:1233– 1239 7. Inanir S, Unlu M, Okudan B et al (1996) Indium-111 octreotide scintigraphy in patients with bone tumours of the extremities. Eur J Nucl Med 23:987–990 8. Chen CC, Czerwiec FS, Feuillan PP (1998) Visualization of fibrous dysplasia during somatostatin receptor scintigraphy. J Nucl Med 39: 238–240
