Computed tomography (CT) and magnetic resonance imaging (MRI) provide exquisite anatomical detail that can help to differentiate chordoma from other tumors, as discussed in Chapter 10. The strength of molecular imaging, on the other hand, lies in its ability to image biological processes occurring at the cellular and molecular levels. We will review the literature of molecular imaging findings of chordoma, with particular attention paid to the use of fluorine-18 fluorodeoxyglucose (F-18 FDG) positron emission tomography (PET), and discuss the current and future roles of molecular imaging in the management of patients with chordoma.
11.2 Radiopharmaceuticals
Radiopharmaceuticals consist of biomolecules labeled with radionuclides that can be administered by injection, inhalation, or ingestion. The biological portion determines in vivo distribution and kinetics of the target molecular process that can be imaged with gamma camera or PET. The physical characteristics of the radionuclide, such as its mode of decay, half-life, photon energy, etc., determine the instrumentation necessary to image. Although radiochemistry and physics of radionuclides, instrumentation, data acquisition, and image reconstruction are beyond the scope of this chapter, it is helpful to have some understanding of the difference between gamma camera and PET. When the radioisotope portion of the radiopharmaceutical is a single-photon gamma emitter, for instance, technetium 99m (Tc-99m), its localization is detected by a gamma camera that converts photons emitted by the radionuclide, a single photon from a single radionuclide, into a light pulse, which then is converted into an electrical signal that is used to form an image. PET is designed to detect two annihilation photons following positron emission from a single radionuclide, which results in greater sensitivity than with single-photon imaging. Given inherent collimation of coincidence detection and attenuation correction with transmission scan or CT possible when combined with PET, PET images are qualitatively superior to those obtained with a gamma camera. Accurate quantification of radiopharmaceutical uptake such as standardized uptake value (SUV) is possible with PET but not with gamma camera imaging to date.
Radiopharmaceuticals with gamma-emitting radionuclides that have been used to image chordoma in the literature are bone tracers such as Tc-99m hydroxymethylene diphosphonate (HMDP) or Tc-99m methylene diphosphate (MDP), gallium-67 (Ga-67) citrate, and indium-111 (In-111) pentetreotide (also referred to as In-111 octreotide). More recently, PET using F-18 FDG has been used for assessment of chordoma. Investigational positron-emitting radiopharmaceuticals, such as carbon-11 methionine (C-11 MET) and fluorine-18 fluoromisonidazole (F-18 FMISO), have also been used to image chordoma and will be briefly discussed.
11.3 Gamma Camera Imaging
11.3.1 Bone Scan
Bone-seeking agents, though incompletely understood, are felt to localize to bone by (1) blood flow and (2) adsorption onto hydroxyapatite crystals on mineralizing bone surfaces. A bone scan is a whole-body study, then, that can assess tumor vascularity, local extent of the tumor, and possible distant osseous metastatic disease. We found 19 reported cases of spinal chordoma imaged with bone-seeking agents since 1973 to as recently as 2012. 1,2,3,4,5,6,7,8 As 2 of these cases were felt to be uninterpretable, one due to bladder activity 3 and the other due to prior surgery of the primary tumor, 6 there were 17 cases with interpretable bone scan findings. All except one (thoracic chordoma) 1 were sacrococcygeal chordomas. All but one bone scan was performed before the resection of the primary tumor. Bone scan was essentially normal with no discernibly increased or decreased tumor uptake and no detectable peripheral bone reaction in three cases. 3,4,6 Four cases demonstrated decreased uptake. 1,3,4,5 Seven cases demonstrated mild peripheral increased uptake. 2,3,4,6 Only three cases demonstrated increased uptake. 4,7,8 One case was imaged with single-photon emission computed tomography (SPECT)/CT, 7 whereas the others consisted only of planar imaging.
11.3.2 Gallium Scan
Ga-67 citrate has been utilized to evaluate a variety of conditions, including tumors such as hepatocellular carcinoma and lymphoma as well as infections such pneumocystis pneumonia (PCP) in patients with acquired immunodeficiency syndrome (AIDS) and vertebral discitis-osteomyelitis. Although there are several modes of gallium localization, most circulates in plasma bound to transferrin; increased blood flow and capillary permeability allow Ga-67–transferrin complex to be delivered to the sites of inflammation and infection. There are four cases of chordoma evaluated with Ga-67 citrate reported. None of these demonstrated increased uptake. 6
11.3.3 Indium-111 Pentetreotide
In-111 is used to label pentetreotide, a conjugate of octreotide, a somatostatin analogue that binds to somatostatin receptors, predominantly subtypes sst2 and sst5, found on neuroendocrine tumors and some non-neuroendocrine tumors. One chordoma imaged with In-111 pentetreotide demonstrated grade 1 uptake (faint uptake similar to that of the skull). 9 One other chordoma patient was imaged with this radiopharmaceutical. 10 This was a patient with clival chordoma who underwent multiple treatments, including excisions, radiation, brachytherapy, as well as chemotherapy, in the 15-year course of her disease for multiple recurrences and metastatic disease. Whereas local recurrence demonstrated faint to moderate uptake on In-111 pentetreotide scan, lung metastases demonstrated intense uptake. This scan was performed to plan a radionuclide receptor-targeted radiotherapy with yttrium 90–labeled lanreotide conjugate (Y-90-DOTA-lanreotide). Like pentetreotide, lanreotide is a somatostatin analogue with high affinity for sstr2, sstr3, sstr4, and sstr5. Y-90 is a high-energy beta particle–emitting radionuclide used to label compounds for radionuclide therapies, for example, radioembolization of unresectable liver tumors with Y-90 microspheres. Cross-sectional imaging performed 2 months afterward demonstrated stable disease in the lungs but progression of the skull base lesions, reflecting greater efficacy of radionuclide receptor-targeted therapy corresponding to the degree of somatostatin receptor expression as reflected on the In-111 pentetreotide imaging.
11.4 Positron Emission Tomography
11.4.1 F-18 FDG
F-18 FDG is a glucose analogue that is transported by glucose transporters into the cells by glucose transport proteins (glucose transporter [GLUT]) where they are phosphorylated by hexokinase. Unlike normal glucose, however, FDG cannot be further metabolized to enter the glycolytic pathway, thus effectively becoming trapped in the cell as FDG-6-phosphate. Increased vascularity of the tumor delivering more radiopharmaceutical, increased GLUT1 with more movement of FDG into the cell, more hexokinase with increased FDG-6-phosphate production and trapping, as well as decreased glucose-6-phosphatase leading to less intracellular dephosphorylation of FDG-6-phosphate and less removal of FDG out of the malignant cell are all thought to contribute to increased FDG uptake in tumor cells. Increased FDG uptake can also be seen in inflammatory or infectious conditions as well as certain benign tumors.
Evaluation of Spinal Mass
Initial reports of patients with chordoma imaged with F-18 FDG PET were of those with as yet undiagnosed symptomatic spinal masses. Three such case reports have been published. 11,12,13 All of the three sacrococcygeal masses reported in these case reports demonstrated moderately intense, heterogeneous FDG uptake with SUVmax of 4.5 in one report, 5.8 in another report, and unavailable in the third.
Recurrent Disease
F-18 FDG PET/CT evaluation has been shown to demonstrate uptake in recurrent disease and can demonstrate metabolic activity different than that of the primary tumor. When Miyazawa and colleagues reported their one case of thoracic chordoma imaged with F-18 FDG PET/CT, they imaged not only the primary tumor before excision but also its recurrence. The primary tumor before excision demonstrated SUVmax of 2.45. The recurrent tumor that was found 7 months after the initial presentation demonstrated SUVmax of 4.36. 14
Metastatic Disease
F-18 FDG PET/CT is generally performed from base of the skull to midthigh for oncologic evaluation. In patients with chordoma, F-18 FDG PET/CT has demonstrated uptake in regional and distant metastatic diseases, including those not suspected by clinical presentation or anatomical imaging alone originating not only from the spine, but also from the skull base.
Two years after the resection and a course of proton beam radiation therapy (RT) of a primary chordoma involving C3–C5, a patient with new lymphatic mass in the neck underwent F-18 FDG PET/CT. The F-18 FDG PET/CT demonstrated uptake not only in the known neck mass (SUVmax = 5.2) but also in another cervical lymph node not identified by MRI prospectively; both lymph nodes were excised and were proven to be chordoma metastases. 15
Two patients with metastatic disease from sacrococcygeal chordoma were imaged with F-18 FDG PET/CT. F-18 FDG PET/CT demonstrated the recurrence in the pelvis (SUVmax = 12.9) and multiple pulmonary metastases (SUVmax = 8.3) as well as an abdominal wall nodule (SUVmax = 3.4) in one patient, 16 whereas in the other patient, it demonstrated local recurrence with widespread metastatic disease involving the adrenal gland, liver, and skeletal muscle. 17
Although F-18 FDG PET/CT is felt to be limited in evaluating brain and skull base tumors such as chordoma due to high background physiologic uptake, it demonstrated persistent spheno-occipital chordoma (SUVmax = 5.0) as well as metastatic disease involving the mandible (SUVmax = 5.4), skin, lungs, and axial skeleton, including the spine. 18
Unsuspected Synchronous Tumor
In a patient who presented after the resection of primary sacrococcygeal chordoma, F-18 FDG PET/CT demonstrated mildly FDG-avid ischiorectal fossa masses on both sides, with extension into the left gluteus maximus muscle (SUVmax = 4.8). This patient was then treated with palliative radiotherapy and neoadjuvant chemotherapy with imatinib mesylate, with partial relief of pain and decreased recurrent tumor size. When the patient was found to have a new lytic lesion at T10 5 years later, F-18 FDG PET/CT was performed and demonstrated intense uptake in the distal esophagus (SUVmax = 25) and a paraesophageal node (SUVmax = 17.8), with only mild uptake at T10 (SUVmax = 5.6). Given the significant difference of FDG avidity of T10 from that of the esophagus and adjacent lymph node, biopsy of the esophagus and T10 lesion was performed, and found primary esophageal adenocarcinoma and T10 chordoma metastasis. 16
Change of Presumed Diagnosis of Chordoma
F-18 FDG PET/CT has been shown to change diagnosis of patients with presumed chordoma based on anatomical imaging alone. One patient with a clival mass felt to be a chordoma based on CT and MRI was found to have multiple lesions on F-18 FDG PET/CT and pathologic diagnosis came back as multiple myeloma, 19 whereas another who underwent complete resection of presumed clival chordoma with pathologic diagnosis of mucinous adenocarcinoma metastasis was found to have F-18 FDG uptake in the breast and axilla that reflected breast cancer. 20
Although one of the cases reported by the latter group did not have F-18 FDG PET/CT imaging, it is instructive. The patient had history of clival chordoma that was resected and treated with radiotherapy. MRI that was performed after the patient presented with a month of right occipital headache and a stabbing sensation behind the left eye demonstrated a clival lesion. Because the symptoms were presumed to reflect recurrent chordoma, the patient underwent endoscopic resection. Pathology excluded chordoma but supported diagnosis of metastatic leiomyosarcoma. This patient, in addition to history of chordoma, had history of metastatic lower extremity leiomyosarcoma with liver, lung, and bone metastases that had been stable for 2 years. Had F-18 FDG PET/CT been performed, correct diagnosis might have been made before the surgery.
Assessment of Therapy Response
F-18 FDG PET/CT has been shown to be useful in evaluating tumor response to therapy, with potential to alter the course of therapy as well as to provide prognostic information in many tumors. Although complete local control of chordoma is felt to confer best prognosis, systemic therapy has been attempted and F-18 FDG was utilized in the evaluation of response to imatinib mesylate (Gleevec; Novartis Pharmaceutics Corporation), an inhibitor of several tyrosine kinases. Five of six patients with advanced chordoma were evaluated with F-18 FDG PET 1 to 8 months following initiation of therapy with imatinib mesylate. There was decreased uptake in all five patients. 21 Additional studies reported use of F-18 FDG PET to assess response to therapy. Ten patients with locally advanced or metastatic unresectable chordomas were treated with imatinib mesylate and sirolimus (rapamycin), an immunosuppressant, with 89% demonstrating clinical benefit; of the nine patients who were evaluated with baseline and follow-up F-18 FDG PET, seven demonstrated F-18 FDG PET response. 22 A phase II clinical study of 56 patients with advanced chordoma treated with imatinib mesylate evaluated multiple parameters including F-18 FDG PET response. 23
11.4.2 Other PET Imaging Tracers
C-11 MET
C-11 MET is a PET radiopharmaceutical that can assess tumor proliferation and has been used to image patients with chordoma. Methionine is a naturally occurring essential amino acid that is transported into cells by L-type amino acid transporter 1 (LAT1), which is necessary for phospholipid synthesis and protein formation. C-11 MET uptake has been shown to correlate with cell proliferation in cell culture, Ki-67 expression, and proliferating cell nuclear antigen expression, a marker of tumor proliferation. 24 Fifteen patients with chordomas (2 pelvic, 11 sacral, 1 thoracic, and 1 thigh) were evaluated with C-11 MET PET/CT before and after carbon ion radiotherapy (CIRT). 25 Baseline C-11 MET PET/CT clearly identified 12/15 (80%) chordomas. All patients underwent follow-up C-11 MET PET/CT 1 month after CIRT, with 11 of the 12 chordomas demonstrating decreased MET uptake. Fourteen (93%) of these 15 patients showed no local recurrence after CIRT, with median follow-up of 20 months. The authors suggested that C-11 MET PET/CT may be a useful biological marker for therapeutic monitoring of chordoma.
F-18 FMISO
Hypoxia has long been known to confer resistance to RT. 26,27 F-18 FMISO is an accurate marker of regional hypoxia, with the long history leading to its creation and investigations well discussed by Rajendran and Krohn. 28 Boost radiation to hypoxic subvolumes can now be delivered with intensity-modulated radiotherapy. With this in mind, F-18 FMISO FDG PET/CT has been used to evaluate patients with chordoma. Seven patients with incompletely resected skull base chordoma were evaluated with F-18 FMISO and F-18 FDG PET/CT before the planned high-dose RT. Whereas on F-18 FDG PET only one lesion was visible, seven of nine lesions were visible with F-18 FMISO PET/CT, indicating the presence of hypoxia. 29 In a prospective pilot study of 20 patients with primary or locally recurrent chordoma treated with proton or combined proton–photon RT with or without surgery, F-18 FMISO PET/CT was performed before and during RT. 30 Hypoxic subvolumes were detected in 9 patients before RT and in 10 patients at interval FMISO PET/CT during RT. Hypoxic subvolumes were cumulatively detected in 12/20 patients (60%). Those with demonstration of hypoxic subvolumes had significantly larger tumor volumes and were more likely to have stage T2 tumors. Local recurrence was not detected during the median follow-up of 1.8 years at the time of their report. Of the three patients who developed metastatic disease, hypoxic tumor volumes were seen in two. Eight of 12 (66.7%) hypoxic subvolumes identified by F-18 FMISO PET/CT were large enough to allow an intensity-modulation proton therapy boost with potential to improve outcome.
11.5 Conclusion
There are a handful of case reports of molecular imaging of this rare tumor. Of all reported cases of gamma camera imaging of chordoma, most were bone and gallium scans. Bone scan has shown variable pattern of uptake, including decreased uptake, increased uptake, and no obvious increased or decreased uptake with or without peripherally increased uptake, whereas gallium scan has shown no abnormal uptake. Gallium scan has virtually been replaced by F-18 FDG PET/CT for most clinical indications, and its use is not likely to be further investigated. Whereas one of the reported bone scans of chordoma was performed with SPECT/CT, all of the remaining cases were planar bone scans; some published images were of poor quality resulting from the use of an obsolete gamma camera or even a rectilinear scanner. Therefore, the published results may not be generalizable to bone scans that would be obtained with a state-of-the-art system. The more recently introduced SPECT/CT is a robust technology that has been shown to increase both the sensitivity and specificity compared with planar imaging alone in various clinical settings. Additive values of SPECT/CT bone scan in chordoma are currently unknown and may be a subject for further investigation.
With its greater contrast-to-noise ratio of abnormal to normal tissue and ability to detect disease before anatomical changes occur, F-18 FDG PET has a well-established role in initial and subsequent staging of many malignancies. It has also been shown to assess response in the early course of therapy, thus potentially altering its ultimate course, while providing prognostic information by evaluating therapy response after its completion. F-18 FDG PET/CT has been shown to identify primary and recurrent tumors, help guide biopsy, detect regional and metastatic diseases, both anatomically suspected and not, identify secondary malignancy, and offer an alternate, more accurate diagnosis when presumed diagnosis of chordoma is proven wrong. We have seen a case of widespread metastatic disease with marked FDG avidity ( ▶ Fig. 11.1), as well as several cases of chordoma, both recurrent and primary, that did not demonstrate significant FDG uptake at our institution. Most published reports are case reports. It is also possible that only positive cases on FDG-PET may have been selectively published. Given the absence of a large series of this rare tumor studied with F-18 FDG PET/CT, the role of F-18 FDG PET/CT is not well defined.
Fig. 11.1 Markedly FDG-avid metastatic nodules and masses in both lungs and in the left obturator foramen. Incidental finding of polycystic kidney disease. (Image courtesy of Dr. Saurabh Rohatgi.)
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