- Email: [email protected]
CT Imaging in Oncology
PII S1095-0397(01)00055-3
Clinical Positron Imaging Vol. 3, No. 6, 223–230. 2000 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved. 1095-0397/00 $–see front matter
ORIGINAL ARTICLE
Combined PET/CT Imaging in Oncology: Impact on Patient Management Paul G. Kluetz, BS1, Carolyn Cidis Meltzer, MD1,2, Victor L. Villemagne, MD1, Paul E. Kinahan, PhD1, Subhash Chander, MD1, Marsha A. Martinelli, CNMT1, David W. Townsend, PhD1 Department of 1Radiology and 2Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15213 Purpose: In this work, we describe five oncology patients whose clinical management were uniquely benefited by a novel scanner that acquires positron emission tomography (PET) and x-ray computed tomography (CT) in the same imaging session. Procedures: Co-registered 2-[F18]-fluoro-2-deoxy-D-glucose (FDG)-PET and CT images were acquired using a combined PET/CT scanner. Pathology and clinical follow-up data were used to confirm PET/CT scan results. Results: The combined PET/CT scanner demonstrated the ability to distinguish malignant lesions from normal physiologic FDG uptake in the striated muscles of the head and neck as well as excretory and bowel activity in the abdomen and pelvis. Additionally, the technology positively affected patient management through localization for surgical and radiation therapy planning as well as assessment of tumor response. Conclusion: Our experience indicates that simultaneous acquisition of co-registered PET and CT images enabled physicians to more precisely discriminate between physiologic and malignant FDG uptake and more accurately localize lesions, improving the value of diagnostic PET in oncologic applications. (Clin Pos Imag 2000;3:223–230) © 2001 Elsevier Science Inc. All rights reserved. Key Words: Combined PET/CT; FDG-PET; Positron emission tomography; Image fusion.
Introduction
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hole-body PET scanning with the radiolabeled glucose analog 2-[F18]-fluoro-2-deoxyD-glucose (FDG) plays an important role in the diagnosis and management of cancer. FDG accumulation detected by PET has been shown to be a reliable method for assessing the glucose metabolic rate of human cells.1,2 Given that many malignant cells exhibit elevated glucose metabolism,3 FDG-PET has been used in the primary staging and therapeutic monitoring of cancer. Due to its high sensitivity, FDG-PET can distinguish malignant from benign lesions and can identify areas of cancerous involvement.4 Indeed, FDG-PET can accurately detect a number of different malignancies including lymphoma and melanoma, as well as lung, colorectal, and head and neck tumors.5–9 However, the clinical interpretation of FDG-PET scans can be confounded by normal physiologic accumulation of FDG. Address correspondence to: Carolyn Cidis Meltzer, M.D., University of Pittsburgh Medical Center, PET Facility, B-938, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA. Tel.: 1-412-647-0736; Fax: 1-412-647-0700; E-mail address: [email protected]
Variable physiologic FDG uptake occurs in the digestive tract, thyroid gland, striated muscle, myocardium, bone marrow, brain and genitourinary tract.10,11 In particular, the neck, abdomen and pelvis can be challenging areas to distinguish physiologic muscle and organ uptake from tumor. While knowledge of the normal distribution of FDG uptake is paramount to the accurate interpretation of whole-body PET images, it is often difficult to confidently identify an area as normal or pathologic with the limited anatomic landmarks provided by PET alone. This fact, coupled with the benefit of localization for proper staging and surgical planning, necessitates the use of anatomic images in the evaluation of PET studies. Normal physiologic uptake in an FDG-PET scan may be misinterpreted as a false positive result or mask a nearby malignant lesion. It has been shown that the visual correlation of PET with CT can improve the accuracy of PET alone.12 Furthermore, CT or magnetic resonance (MR) images have been retrospectively fused to simultaneously display registered anatomic and metabolic information.13 Fusion images can improve the accuracy of tumor detection over visual cor223
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relation of the two images separately,14,15 however, the repositioning of the patient and time interval between scans makes the co-registration of separately obtained images difficult and inherently imprecise. In order to realize the benefits of anatomic information while addressing the problems associated with retrospective image fusion, a novel combined PET/CT scanner has been built.16 With the combined PET/CT scanner, the patient undergoes a spiral CT scan followed immediately by a PET scan during the same imaging session. This method addresses the patient repositioning and temporal problems associated with retrospective fusion methods, providing more precise coregistration of the two images. Additionally, the CT scan can be used to provide low noise PET attenuation correction factors and scatter correction, thus improving quantitative PET imaging crucial for serial studies assessing tumor response to therapy.17 We illustrate five clinical situations where the combined PET/CT tomograph was critical to the accurate interpretation of PET data. Specific examples of physiologic FDG uptake are illustrated and the ability of PET/CT to discriminate tumor from normal uptake is addressed. Additionally, we discuss the impact of the combined PET/CT on the patients’ surgical and medical management.
can also display the PET and CT images in fused mode. All images can be viewed in the transverse, sagittal or coronal planes. Subjects were selected from the over 175 patients who have been scanned with the combined PET/CT tomograph at the University of Pittsburgh PET facility. Representative subjects were chosen who demonstrated a range of difficult clinical PET scenarios in which the combined PET/CT images were crucial for the accurate assessment of the PET results. All patients were enrolled in an Institutional Review Board (IRB) approved research protocol at the University of Pittsburgh. Each patient was informed about the procedure and its associated risks and benefits and written informed consent was obtained. The patients were injected with between 6.5mCi and 7.3mCi of FDG. Cases 1 and 2 underwent a PET/CT alone and were scanned after a 57–73 min uptake period. Cases 3–5 were scanned on the PET/CT tomograph following a standard whole-body clinical PET scan on an ECAT ART scanner conducted one hour post injection. As such, the uptake period for the combined PET/CT scans in cases 3–5 was between 150 and 197 min.
Subjects Case 1
Subjects and Methods PET/CT Scanner and Acquisition The novel combined PET/CT scanner used in this work is described in detail by Beyer et al.16 Briefly, the combined PET/CT tomograph is comprised of a Siemens Somatom AR.SP spiral CT and a partial ring, rotating ECAT ART PET scanner housed in a single gantry. PET and CT images can be acquired for an axial extent of 100cm, which is sufficient to allow scanning from the chin to the lower thigh. The scanning session begins after the injection of the desired radiolabeled tracer with a 5–10 min CT scan. In addition to providing excellent anatomic detail, the CT scan is used to correct the PET data for scatter and attenuation.18 The CT scan is not significantly affected by the post-injection radioactive emission of the patient, and its use for PET attenuation correction is thought to be a major benefit of the combined PET/CT technology.17 Following the spiral CT scan, the scanning bed is repositioned and a 45-60 min PET scan is conducted. The patient remains positioned on the scanning bed for the entire duration of the PET/CT acquisition. CT-based attenuation and scatter correction are applied to the PET emission data, and the corrected data reconstructed with the FORE OSEM algorithm.19 The CT and PET images are displayed for reading in adjacent windows of a PET/CT viewing tool. The CT windows
This 34-y-old man was diagnosed with squamous cell carcinoma of the right hard palate and gingiva in December of 1998. Tumor resection was performed and chemotherapy and radiation therapy were subsequently administered. Recurrence diagnosed 7 mo later in the right cheek and neck was surgically treated with a right maxillectomy. Radiation and chemotherapy were again administered. In February of 2000, a follow-up CT of the head and neck revealed abnormal enhancement involving the right parotid, masticator space, pterygopalatine fossa and temporalis muscle. This CT also suggested possible metastasis of the right mandibular ramus but could not distinguish between recurrent tumor or radiation damage in the remainder of the abnormal tissue. A PET/CT was completed on the same day and demonstrated focally elevated FDG accumulation in the right infratemporal fossa. The combined scan localized the tumor to include the right mandibular ramus and the soft tissue immediately medial and lateral to the bone (Figure 1A). In addition, the lesion appeared to be anterolateral to the vascular space and did not include the bulk of the temporalis muscle. Approximately 2 weeks later, a right mandibulectomy was performed to excise the recurrent tumor. Histopathologic examination revealed squamous cell carcinoma in the right mandible and maxilla involving the retromolar trigone, buccal mucosa, floor of the mouth, and base of the tongue. Four months later, a second PET/CT exam re-
Combined PET/CT in Oncology / Kluetz et al. 225
vealed a small focus of moderately elevated FDG uptake in the subcutaneous tissue at the right posterior aspect of the surgical bed at the C2-C3 level suspicious for disease (Figure 1B). Surgery was planned to investigate this area and the excised tissue was found to be positive for residual disease.
tissue mass that appeared to involve the paraspinal muscle. There was no evidence of abnormal accumulation outside of this site. Following the PET/CT, chemotherapy was administered and a radiation port was chosen appropriate to the post-surgical staging made possible by the PET/CT results.
Case 2
Case 4
This 60-y-old man was diagnosed with squamous cell carcinoma of the base of the tongue with involvement of left cervical lymph nodes in March of 1998. A treatment course consisting of chemotherapy and concurrent radiation was administered in addition to brachytherapy. Nearly two years after his diagnosis, following CT suspicion of recurrence in a left jugulodigastric node and the left tongue base, a CT-guided needle biopsy was positive for recurrent disease in the lymph node but non-diagnostic in the floor of the mouth. One month later, a PET/CT scan was acquired which revealed increased focal FDG uptake corresponding to the confirmed left jugulodigastric node (Figure 2A), but also showed markedly increased uptake over a soft tissue fullness at the left base of the tongue and floor of mouth over the submental muscles (Figure 2C). Recurrence was diagnosed and the patient was entered into a gene therapy protocol. Three months later, a second PET/CT scan showed increasing uptake corresponding to the left base of tongue mass. The standard uptake value (SUV) of the lesion had increased from 4 to 7.5 and the size was unchanged or slightly larger than that seen on the earlier PET/CT scan. The FDG uptake in the floor of the mouth was deemed physiologic as it remained stable and again appeared to correspond to the submental muscles visualized on CT. The jugulodigastric node seen in the previous PET/CT study had substantially increased in both size and FDG uptake (SUV of 3.5–4.0 compared to 2.5 on previous study, Figure 2B). Gene therapy was discontinued due to progression of disease and the patient was informed of new therapy options.
This 50-y-old woman was diagnosed with primary adenocarcinoma of the left fallopian tube in 1996 and underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. In early 1997 she presented with left inguinal lymphadenopathy which was biopsied and confirmed to be metastatic adenocarcinoma. Five cycles of chemotherapy were completed. The patient did well until November 1998 when an abdominal CT revealed left and right inguinal lymphadenopathy. Excisional biopsy confirmed recurrent adenocarcinoma. Pelvic and inguinal radiotherapy was undertaken and both nodules resolved. A follow-up CT scan of the abdomen and pelvis in December 1999 showed no evidence of disease. In response to a rising serum CA-125 marker 3 mo later, a clinical whole-body PET scan performed on an ECAT ART scanner was immediately followed by a combined PET/CT scan to assess for recurrent disease. The clinical whole-body PET scan revealed a focus of moderate FDG elevation superolateral to the bladder on the left. This finding was equivocal using the clinical PET scan alone, as benign etiology such as ureteral diverticulum might also explain the result. However, the PET/CT scan performed directly after the clinical study localized the lesion to the superolateral left pelvis, in the region of the obturator lymph node chain, revealing that this uptake was separate from and lateral to the ureter (Figure 4). Following the PET/CT results, a laparatomy was performed and a tissue mass was located in the left obturator lymph node area, consistent with the localization obtained by the combined PET/CT. The tumor was debulked and surgical pathology verified malignancy.
Case 3
Case 5
This 56-y-old man presented in February of 2000 with complaints of pain in the neck and medial border of the left scapula accompanied by numbness and tingling in the left hand. Lytic destruction of the C6 vertebral body was noted on a CT of the cervical spine. One month later, the patient underwent a C6 corpectomy with anterior cervical fusion and allograft. Surgical pathology diagnosed the excised tissue as a malignant B-cell lymphoma. A PET/CT was acquired to assess the extent of the lymphoma for staging and therapeutic planning. The PET/CT localized substantially elevated FDG (SUV 8-9) in the left lamina of the C6 vertebrae (Figure 3). This uptake extended into a left lateral soft
This 55-y-old man presented with left inguinal lymphadenopathy, which was biopsied in March of 2000 and found to be positive for low-grade malignant lymphoma. A CT of the chest, abdomen and pelvis performed approximately 2 weeks later demonstrated adenopathy around the distal aspect of the abdominal aorta at the level of the bifurcation with the largest node measuring 2.5 cm. No other masses were identified. Approximately 3 weeks following the CT, a clinical whole-body FDGPET scan performed on the ECAT ART scanner showed multifocal bilateral FDG accumulation in the groin and pelvis. Also noted was bilateral curvilinear FDG uptake in the abdomen and pelvis consistent with
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Figure 1. Case 1 PET/CT scans, transverse view. The initial scan showed FDG elevation involving the mandibular ramus (A). A repeat scan conducted 4 months later demonstrated significant postsurgical changes with a focus of FDG uptake in the right neck, posterior to the surgical bed (B).
Figure 2. Case 2 PET/CT scans, transverse view. The initial PET/CT scan revealing elevated FDG accumulation in a jugulodigastric node (A). A follow-up PET/CT scan conducted 3 months later showed an increase in the intensity of FDG uptake in the same lymph node, indicating disease progression (B). FDG uptake in the floor of the mouth, shown here from the initial PET/CT scan (C), was deemed physiologic as it remained stable through the two scans and appeared to correspond to submental muscle.
Combined PET/CT in Oncology / Kluetz et al. 227
Figure 3. Case 3 PET/CT scans. In the sagittal view (A), focal FDG uptake was localized to the area of the C6 corpectomy site. The transverse view of the same PET/CT scan (magnified to area of interest) revealed involvement in the surgical site (B), as well as the left lamina of C6 with extension into the paraspinal muscle (C).
Figure 4. Case 4 PET/CT scan, transverse view. Following a full body PET scan that was equivocal for malignancy due to potential urinary excretion artifact, this PET/CT scan localized a focal area of increased FDG uptake to the region of the obturator lymph node chain, separate from and lateral to the ureter.
Figure 5. Case 5. The transverse view of the PET/CT scan shows focal areas of FDG uptake corresponding to adenopathy seen on the CT component (A). The coronal view of the full body clinical PET scan of this patient, conducted just prior to the PET/CT scan, was equivocal for adenopathy vs. benign ureteral excretion (B). This pattern of uptake was strikingly similar to the negative whole-body clinical PET scan of a man with benign prostatic hypertrophy (C).
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para-aortic and pelvic adenopathy. However, bilateral ureteral accumulation of tracer along the para-aortic region extending into the pelvis could not be excluded (Figure 5B). A PET/CT scan was acquired subsequent to the whole body PET scan (Figure 5A). The bilaterally symmetric abdomenopelvic uptake was clearly shown to correspond to para-aortic and illiac adenopathy with PET/CT.
Discussion The cases presented in this report demonstrate some of the benefits that may be realized by combined PET/CT imaging. By acquiring both images in the same session, the patient does not need to be moved from the scanning bed, thus eliminating changes in position that lead to misregistration of PET and CT images. This becomes particularly important for head and neck imaging, where changes in neck position have been shown to affect retrospective fusion of PET and MRI images and result in misalignment.20 In addition, near-simultaneous acquisition of the two scans eliminates the possibility of a new lesion seen on PET that has developed after the acquisition of the CT scan. Combined PET/CT scanning has proven to be useful at our center for the discrimination of physiologic from malignant FDG uptake. In the head and neck, FDG accumulation can be due to normal uptake in striated muscles such as the sternocleidomastoid.10 In addition, it has been shown that speaking during the uptake phase leads to accumulation in the laryngeal muscle.21,22 Even if the patient is instructed to limit speaking during the FDG uptake phase, lack of compliance, stress or anxiety often produce pronounced physiologic uptake that may confound PET interpretation. Bilateral, curvilinear FDG uptake supports benign muscle activity. However, malignant lymph node chains may produce similar patterns. The PET/CT scanner is able to accurately localize FDG uptake to masses outside of muscle planes, significantly enhancing the ability to discriminate between benign muscle uptake and malignancy. In cases 1 and 2, the patients presented with head and neck malignancies (Figures 1 and 2). In these cases, combined PET/CT localized the focal malignant FDG uptake to soft tissue masses outside of striated muscle planes. Additionally, case 2 demonstrates significant FDG accumulation in the floor of the mouth directly over submental muscle planes (Figure 2C). The fact that the FDG accumulation was bilateral and localized to the submental muscles, in addition to the stability of the FDG uptake in the follow up PET/CT scan while the lymph node and tongue lesions were progressing, supports the conclusion that the floor of the mouth finding is likely due to physiologic submental muscle uptake. With the added anatomic information provided by CT,
combined PET/CT may improve the specificity of FDGPET results in head and neck malignancies. While PET images of the head and neck can be confounded by physiologic muscle uptake, CT or MRI images of this region can also be difficult to interpret. Evaluation of head and neck cancer using CT or MRI alone can be challenging if significant post-surgical and/or post-radiation changes exist. In case 1, the patient had undergone resection before both PET/CT scans, distorting normal anatomy and making an analysis of CT or MRI difficult. In particular, the post-mandiblectomy scan in case 1 would have been difficult to evaluate for recurrence using a follow up CT scan alone (Figure 1B). By combining PET’s ability to discriminate post-surgical changes and radiation damage from disease with CT’s anatomic information to localize FDG uptake, interpretation of the combined images can be more accurate. Another area where normal physiologic uptake is a concern is the abdomen and pelvis. Here, excretion of FDG in the kidneys, ureters and bladder can be mistaken for tumor or can mask a nearby malignant lesion.11 Additionally, the normal bowel has been shown to demonstrate variable benign FDG accumulation.23–25 In cases 4 and 5, FDG uptake on a conventional wholebody PET scan alone was equivocal because of the proximity of the bladder and ureters to the lesion. However, with the anatomic data provided by PET/CT, malignant lesions were definitively confirmed. Case 4 demonstrates a focal area of FDG uptake immediately adjacent to the bladder, which was diagnosed as malignant pelvic adenopathy by PET/CT (Figure 4). In case 5, a conventional whole-body PET scan showed bilateral curvilinear FDG accumulation that was difficult to discriminate from ureteral excretion. Figure 5 demonstrates the similarity between the FDG uptake patterns seen in two conventional whole-body FDG PET scans: that of case 5, and the scan of a patient with benign ureteral excretion due to prostatic hypertrophy completed the same day. The side-by-side comparison of the two clinical PET scans (Figure 5B and 5C) is an example of the difficulty in discriminating malignancy from physiologic excretion in the abdomen. The combined PET/CT in case 5 correctly diagnosed bilateral adenopathy, easily discriminating tumor from physiologic ureteral activity (Figure 5A). In our experience, the use of PET/CT has had a significant impact on patient management. In particular, we have received excellent feedback from our surgical colleagues with respect to the utility of PET/CT scans. For example, in case 1, the first PET/CT scan identified the area of elevated FDG as involving the mandible (Figure 1A) but sparing the temporalis muscle and vascular bundle. By pinpointing the areas of involvement, the surgeon was better able to define margins and spare structures that were not affected by malignancy.
Combined PET/CT in Oncology / Kluetz et al. 229
In addition, the follow-up PET/CT study for this patient isolated a small residual lesion that was also surgically removed and found to be positive for tumor (Figure 1B). Due to the small size of the ulcerated lesion (1.5 cm 1.0 cm) and the significant post surgical changes in the area, this lesion may have been missed using CT follow up alone. In case 4, the PET/CT scan was also used effectively for surgical planning. In this case, laparatomy was successfully directed to the FDG focus in the left obturator lymph area. During the exploratory portion of the laparotomy the pelvis and abdomen were found to be negative for tumor and the surgeon may have ended the procedure at that point. However, due to the PET/CT results, the surgeon then proceeded directly to the left obturator lymph area and located and debulked the tumor. Another aspect of patient management where combined PET/CT can be beneficial is in evaluating response to therapy. Case 2 is an example of the use of PET/CT in therapeutic management. After the initial PET/CT scan helped to localize recurrence to the tongue base and left jugulodigastric node (Figure 2A), the patient was placed on a gene therapy protocol. The follow-up PET/CT scan administered 3 mo later showed an increase in intensity in the FDG uptake at the jugulodigastric node (Figure 2B) and tongue base. The finding indicated poor response to the therapy and the gene protocol was discontinued and an alternative treatment was sought. Case 3 is an example of the post-operative staging of a C6 lymphoma. Because the FDG uptake was isolated to the region of the surgical bed, a less aggressive form of chemotherapy was chosen. Additionally, accurate localization of the disease by PET/CT allowed the radiation port to be efficiently placed.
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Conclusion The cases illustrated in this review suggest that PET and CT images acquired in the same scanning session by a PET/CT scanner may improve both the accuracy and utility of PET image interpretation. In our experience, these accurately co-registered PET and CT images have helped to discriminate areas of physiologic uptake from malignant lesions in situations where conventional PET or CT alone was equivocal. In addition, the PET/CT scanner eliminates the co-registration of a PET scan with anatomic information from a CT or MRI that may have changed in the time between scans. Finally, precisely localized PET information can be used to plan surgical and medical therapy and in so doing, improve the management of patients with malignant disease.
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References 1. Phelps, M.E.; Huang, S.C.; Hoffman, E.J.; Selin, C.; Sokoloff, L.; Kuhl, D.E. Tomographic measurement of
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local cerebral glucose metabolic rate in humans with (F-18)2-fluoro-2-deoxy-D-glucose: validation of method. Ann. Neurol. 1979;6(5):371–88. Huang, S.C.; Phelps, M.E.; Hoffman, E.J.; Sideris, K.; Selin, C.J.; Kuhl, D.E. Noninvasive determination of local cerebral metabolic rate of glucose in man. Am. J. Physiol. 1980;238(1):E69–82. Smith, T.A. FDG uptake, tumour characteristics and response to therapy: a review. Nucl. Med. Commun. 1998; 19(2):97–105. Delbeke, D. Oncological applications of FDG PET imaging: brain tumors, colorectal cancer, lymphoma and melanoma. J. Nucl. Med. 1999;40(4):591–603. Marom, E.M.; McAdams, H.P.; Erasmus, J.J.; et al. Staging non-small cell lung cancer with whole-body PET. Radiology 1999;212(3):803–9. Bangerter, M.; Moog, F.; Buchmann, I.; et al. Whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin’s disease. Ann. Oncol. 1998;9(10):1117–22. Macfarlane, D.J.; Sondak, V.; Johnson, T.; Wahl, R.L. Prospective evaluation of 2-[18F]-2-deoxy-D-glucose positron emission tomography in staging of regional lymph nodes in patients with cutaneous malignant melanoma. J. Clin. Oncol. 1998;16(5):1770–6. Abdel-Nabi, H.; Doerr, R.J.; Lamonica, D.M.; et al. Staging of primary colorectal carcinomas with fluorine-18 fluorodeoxyglucose whole-body PET: correlation with histopathologic and CT findings. Radiology 1998;206(3):755–60. Adams, S.; Baum, R.P.; Stuckensen, T.; Bitter, K.; Hor, G. Prospective comparison of 18F-FDG PET with conventional imaging modalities (CT, MRI, US) in lymph node staging of head and neck cancer. Eur. J. Nucl. Med. 1998;25(9):1255–60. Engel, H.; Steinert, H.; Buck, A.; Berthold, T.; Huch Boni, R.A.; von Schulthess, G.K. Whole-body PET: physiological and artifactual fluorodeoxyglucose accumulations. J. Nucl. Med. 1996;37(3):441–6. Shreve, P.D.; Anzai, Y.; Wahl, R.L. Pitfalls in oncologic diagnosis with FDG PET imaging: physiologic and benign variants. Radiographics 1999;19(1):61–77; quiz 150–1. Vansteenkiste, J.F.; Stroobants, S.G.; Dupont, P.J.; et al. FDG-PET scan in potentially operable non-small cell lung cancer: do anatometabolic PET-CT fusion images improve the localisation of regional lymph node metastases? The Leuven Lung Cancer Group. Eur. J. Nucl. Med. 1998;25(11):1495–501. Wahl, R.L.; Quint, L.E.; Cieslak, R.D.; Aisen, A.M.; Koeppe, R.A.; Meyer, C.R. “Anatometabolic” tumor imaging: fusion of FDG PET with CT or MRI to localize foci of increased activity. J. Nucl. Med. 1993;34(7):1190–7. Wahl, R.L.; Quint, L.E.; Greenough, R.L.; Meyer, C.R.; White, R.I.; Orringer, M.B. Staging of mediastinal nonsmall cell lung cancer with FDG PET, CT, and fusion images: preliminary prospective evaluation. Radiology 1994; 191(2):371–7. Magnani, P.; Carretta, A.; Rizzo, G.; et al. FDG/PET and spiral CT image fusion for medistinal lymph node assessment of non-small cell lung cancer patients. J. Cardiovasc. Surg. 1999;40(5):741–8. Beyer, T.; Townsend, D.W.; Brun, T.; et al. A Combined
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PET/CT Scanner for Clinical Oncology. J. Nucl. Med. 2000;41(8):1364–1374. Townsend, D.W.; Beyer, T.; Kinahan, P.E.; et al. Recent studies with a combined PET/CT scanner. In: Tsukamato, E., Kuge, Y., Katoh, C., Morita, K., editors. International Congress Series, 24th–26th September 1999, Hokkaido, Japan. Amsterdam: Elsevier Science B.V. p 229–44. (International Congress Series). Kinahan, P.; Townsend, D.; Beyer, T.; Sashin, D. Attenuation correction for a combined 3D PET/CT scanner. Med. Phys. 1998;25:2046–53. Kinahan, P.; Michel, C.; Defrise, M.; et al. Accelerated statistical reconstruction methods for PET and coincidence-SPECT wholebody oncology imaging. J. Nucl. Med. 1997;38:102. Uematsu, H.; Sadato, N.; Yonekura, Y.; et al. Coregistration of FDG PET and MRI of the head and neck using normal distribution of FDG. J. Nucl. Med. 1998;39(12):2121–7. Heller, M.; Meltzer, C.; Fukui, M.; et al. Superphysiologic
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FDG uptake in the non-paralyzed vocal cord: resolution of a false-positive PET result with combined PET/CT imaging. Clin. Positron Imaging (in press, 2001). Kostakoglu, L.; Wong, J.C.; Barrington, S.F.; Cronin, B.F.; Dynes, A.M.; Maisey, M.N. Speech-related visualization of laryngeal muscles with fluorine-18-FDG. J. Nucl. Med. 1996;37(11):1771–3. Vesselle, H.J.; Miraldi, F.D. FDG PET of the retroperitoneum: normal anatomy, variants, pathologic conditions, and strategies to avoid diagnostic pitfalls. Radiographics 1998;18(4):805–23; discussion 823–4. Yasuda, S.; Ide, M.; Takagi, S.; Shohtsu, A. Cancer screening with whole-body FDG PET. Kaku Igaku - Japanese Journal of Nuclear Medicine 1996;33(10):1065–71. Bohdiewicz, P.J.; Scott, G.C.; Juni, J.E.; et al. Indium-111 OncoScint CR/OV and F-18 FDG in colorectal and ovarian carcinoma recurrences. Early observations. Clin. Nucl. Med. 1995;20(3):230–6.
Clinical Positron Imaging Vol. 3, No. 6, 223–230. 2000 Copyright © 2001 Elsevier Science Inc. Printed in the USA. All rights reserved. 1095-0397/00 $–see front matter
ORIGINAL ARTICLE
Combined PET/CT Imaging in Oncology: Impact on Patient Management Paul G. Kluetz, BS1, Carolyn Cidis Meltzer, MD1,2, Victor L. Villemagne, MD1, Paul E. Kinahan, PhD1, Subhash Chander, MD1, Marsha A. Martinelli, CNMT1, David W. Townsend, PhD1 Department of 1Radiology and 2Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, 15213 Purpose: In this work, we describe five oncology patients whose clinical management were uniquely benefited by a novel scanner that acquires positron emission tomography (PET) and x-ray computed tomography (CT) in the same imaging session. Procedures: Co-registered 2-[F18]-fluoro-2-deoxy-D-glucose (FDG)-PET and CT images were acquired using a combined PET/CT scanner. Pathology and clinical follow-up data were used to confirm PET/CT scan results. Results: The combined PET/CT scanner demonstrated the ability to distinguish malignant lesions from normal physiologic FDG uptake in the striated muscles of the head and neck as well as excretory and bowel activity in the abdomen and pelvis. Additionally, the technology positively affected patient management through localization for surgical and radiation therapy planning as well as assessment of tumor response. Conclusion: Our experience indicates that simultaneous acquisition of co-registered PET and CT images enabled physicians to more precisely discriminate between physiologic and malignant FDG uptake and more accurately localize lesions, improving the value of diagnostic PET in oncologic applications. (Clin Pos Imag 2000;3:223–230) © 2001 Elsevier Science Inc. All rights reserved. Key Words: Combined PET/CT; FDG-PET; Positron emission tomography; Image fusion.
Introduction
W
hole-body PET scanning with the radiolabeled glucose analog 2-[F18]-fluoro-2-deoxyD-glucose (FDG) plays an important role in the diagnosis and management of cancer. FDG accumulation detected by PET has been shown to be a reliable method for assessing the glucose metabolic rate of human cells.1,2 Given that many malignant cells exhibit elevated glucose metabolism,3 FDG-PET has been used in the primary staging and therapeutic monitoring of cancer. Due to its high sensitivity, FDG-PET can distinguish malignant from benign lesions and can identify areas of cancerous involvement.4 Indeed, FDG-PET can accurately detect a number of different malignancies including lymphoma and melanoma, as well as lung, colorectal, and head and neck tumors.5–9 However, the clinical interpretation of FDG-PET scans can be confounded by normal physiologic accumulation of FDG. Address correspondence to: Carolyn Cidis Meltzer, M.D., University of Pittsburgh Medical Center, PET Facility, B-938, 200 Lothrop Street, Pittsburgh, PA 15213-2582, USA. Tel.: 1-412-647-0736; Fax: 1-412-647-0700; E-mail address: [email protected]
Variable physiologic FDG uptake occurs in the digestive tract, thyroid gland, striated muscle, myocardium, bone marrow, brain and genitourinary tract.10,11 In particular, the neck, abdomen and pelvis can be challenging areas to distinguish physiologic muscle and organ uptake from tumor. While knowledge of the normal distribution of FDG uptake is paramount to the accurate interpretation of whole-body PET images, it is often difficult to confidently identify an area as normal or pathologic with the limited anatomic landmarks provided by PET alone. This fact, coupled with the benefit of localization for proper staging and surgical planning, necessitates the use of anatomic images in the evaluation of PET studies. Normal physiologic uptake in an FDG-PET scan may be misinterpreted as a false positive result or mask a nearby malignant lesion. It has been shown that the visual correlation of PET with CT can improve the accuracy of PET alone.12 Furthermore, CT or magnetic resonance (MR) images have been retrospectively fused to simultaneously display registered anatomic and metabolic information.13 Fusion images can improve the accuracy of tumor detection over visual cor223
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relation of the two images separately,14,15 however, the repositioning of the patient and time interval between scans makes the co-registration of separately obtained images difficult and inherently imprecise. In order to realize the benefits of anatomic information while addressing the problems associated with retrospective image fusion, a novel combined PET/CT scanner has been built.16 With the combined PET/CT scanner, the patient undergoes a spiral CT scan followed immediately by a PET scan during the same imaging session. This method addresses the patient repositioning and temporal problems associated with retrospective fusion methods, providing more precise coregistration of the two images. Additionally, the CT scan can be used to provide low noise PET attenuation correction factors and scatter correction, thus improving quantitative PET imaging crucial for serial studies assessing tumor response to therapy.17 We illustrate five clinical situations where the combined PET/CT tomograph was critical to the accurate interpretation of PET data. Specific examples of physiologic FDG uptake are illustrated and the ability of PET/CT to discriminate tumor from normal uptake is addressed. Additionally, we discuss the impact of the combined PET/CT on the patients’ surgical and medical management.
can also display the PET and CT images in fused mode. All images can be viewed in the transverse, sagittal or coronal planes. Subjects were selected from the over 175 patients who have been scanned with the combined PET/CT tomograph at the University of Pittsburgh PET facility. Representative subjects were chosen who demonstrated a range of difficult clinical PET scenarios in which the combined PET/CT images were crucial for the accurate assessment of the PET results. All patients were enrolled in an Institutional Review Board (IRB) approved research protocol at the University of Pittsburgh. Each patient was informed about the procedure and its associated risks and benefits and written informed consent was obtained. The patients were injected with between 6.5mCi and 7.3mCi of FDG. Cases 1 and 2 underwent a PET/CT alone and were scanned after a 57–73 min uptake period. Cases 3–5 were scanned on the PET/CT tomograph following a standard whole-body clinical PET scan on an ECAT ART scanner conducted one hour post injection. As such, the uptake period for the combined PET/CT scans in cases 3–5 was between 150 and 197 min.
Subjects Case 1
Subjects and Methods PET/CT Scanner and Acquisition The novel combined PET/CT scanner used in this work is described in detail by Beyer et al.16 Briefly, the combined PET/CT tomograph is comprised of a Siemens Somatom AR.SP spiral CT and a partial ring, rotating ECAT ART PET scanner housed in a single gantry. PET and CT images can be acquired for an axial extent of 100cm, which is sufficient to allow scanning from the chin to the lower thigh. The scanning session begins after the injection of the desired radiolabeled tracer with a 5–10 min CT scan. In addition to providing excellent anatomic detail, the CT scan is used to correct the PET data for scatter and attenuation.18 The CT scan is not significantly affected by the post-injection radioactive emission of the patient, and its use for PET attenuation correction is thought to be a major benefit of the combined PET/CT technology.17 Following the spiral CT scan, the scanning bed is repositioned and a 45-60 min PET scan is conducted. The patient remains positioned on the scanning bed for the entire duration of the PET/CT acquisition. CT-based attenuation and scatter correction are applied to the PET emission data, and the corrected data reconstructed with the FORE OSEM algorithm.19 The CT and PET images are displayed for reading in adjacent windows of a PET/CT viewing tool. The CT windows
This 34-y-old man was diagnosed with squamous cell carcinoma of the right hard palate and gingiva in December of 1998. Tumor resection was performed and chemotherapy and radiation therapy were subsequently administered. Recurrence diagnosed 7 mo later in the right cheek and neck was surgically treated with a right maxillectomy. Radiation and chemotherapy were again administered. In February of 2000, a follow-up CT of the head and neck revealed abnormal enhancement involving the right parotid, masticator space, pterygopalatine fossa and temporalis muscle. This CT also suggested possible metastasis of the right mandibular ramus but could not distinguish between recurrent tumor or radiation damage in the remainder of the abnormal tissue. A PET/CT was completed on the same day and demonstrated focally elevated FDG accumulation in the right infratemporal fossa. The combined scan localized the tumor to include the right mandibular ramus and the soft tissue immediately medial and lateral to the bone (Figure 1A). In addition, the lesion appeared to be anterolateral to the vascular space and did not include the bulk of the temporalis muscle. Approximately 2 weeks later, a right mandibulectomy was performed to excise the recurrent tumor. Histopathologic examination revealed squamous cell carcinoma in the right mandible and maxilla involving the retromolar trigone, buccal mucosa, floor of the mouth, and base of the tongue. Four months later, a second PET/CT exam re-
Combined PET/CT in Oncology / Kluetz et al. 225
vealed a small focus of moderately elevated FDG uptake in the subcutaneous tissue at the right posterior aspect of the surgical bed at the C2-C3 level suspicious for disease (Figure 1B). Surgery was planned to investigate this area and the excised tissue was found to be positive for residual disease.
tissue mass that appeared to involve the paraspinal muscle. There was no evidence of abnormal accumulation outside of this site. Following the PET/CT, chemotherapy was administered and a radiation port was chosen appropriate to the post-surgical staging made possible by the PET/CT results.
Case 2
Case 4
This 60-y-old man was diagnosed with squamous cell carcinoma of the base of the tongue with involvement of left cervical lymph nodes in March of 1998. A treatment course consisting of chemotherapy and concurrent radiation was administered in addition to brachytherapy. Nearly two years after his diagnosis, following CT suspicion of recurrence in a left jugulodigastric node and the left tongue base, a CT-guided needle biopsy was positive for recurrent disease in the lymph node but non-diagnostic in the floor of the mouth. One month later, a PET/CT scan was acquired which revealed increased focal FDG uptake corresponding to the confirmed left jugulodigastric node (Figure 2A), but also showed markedly increased uptake over a soft tissue fullness at the left base of the tongue and floor of mouth over the submental muscles (Figure 2C). Recurrence was diagnosed and the patient was entered into a gene therapy protocol. Three months later, a second PET/CT scan showed increasing uptake corresponding to the left base of tongue mass. The standard uptake value (SUV) of the lesion had increased from 4 to 7.5 and the size was unchanged or slightly larger than that seen on the earlier PET/CT scan. The FDG uptake in the floor of the mouth was deemed physiologic as it remained stable and again appeared to correspond to the submental muscles visualized on CT. The jugulodigastric node seen in the previous PET/CT study had substantially increased in both size and FDG uptake (SUV of 3.5–4.0 compared to 2.5 on previous study, Figure 2B). Gene therapy was discontinued due to progression of disease and the patient was informed of new therapy options.
This 50-y-old woman was diagnosed with primary adenocarcinoma of the left fallopian tube in 1996 and underwent a total abdominal hysterectomy and bilateral salpingo-oophorectomy. In early 1997 she presented with left inguinal lymphadenopathy which was biopsied and confirmed to be metastatic adenocarcinoma. Five cycles of chemotherapy were completed. The patient did well until November 1998 when an abdominal CT revealed left and right inguinal lymphadenopathy. Excisional biopsy confirmed recurrent adenocarcinoma. Pelvic and inguinal radiotherapy was undertaken and both nodules resolved. A follow-up CT scan of the abdomen and pelvis in December 1999 showed no evidence of disease. In response to a rising serum CA-125 marker 3 mo later, a clinical whole-body PET scan performed on an ECAT ART scanner was immediately followed by a combined PET/CT scan to assess for recurrent disease. The clinical whole-body PET scan revealed a focus of moderate FDG elevation superolateral to the bladder on the left. This finding was equivocal using the clinical PET scan alone, as benign etiology such as ureteral diverticulum might also explain the result. However, the PET/CT scan performed directly after the clinical study localized the lesion to the superolateral left pelvis, in the region of the obturator lymph node chain, revealing that this uptake was separate from and lateral to the ureter (Figure 4). Following the PET/CT results, a laparatomy was performed and a tissue mass was located in the left obturator lymph node area, consistent with the localization obtained by the combined PET/CT. The tumor was debulked and surgical pathology verified malignancy.
Case 3
Case 5
This 56-y-old man presented in February of 2000 with complaints of pain in the neck and medial border of the left scapula accompanied by numbness and tingling in the left hand. Lytic destruction of the C6 vertebral body was noted on a CT of the cervical spine. One month later, the patient underwent a C6 corpectomy with anterior cervical fusion and allograft. Surgical pathology diagnosed the excised tissue as a malignant B-cell lymphoma. A PET/CT was acquired to assess the extent of the lymphoma for staging and therapeutic planning. The PET/CT localized substantially elevated FDG (SUV 8-9) in the left lamina of the C6 vertebrae (Figure 3). This uptake extended into a left lateral soft
This 55-y-old man presented with left inguinal lymphadenopathy, which was biopsied in March of 2000 and found to be positive for low-grade malignant lymphoma. A CT of the chest, abdomen and pelvis performed approximately 2 weeks later demonstrated adenopathy around the distal aspect of the abdominal aorta at the level of the bifurcation with the largest node measuring 2.5 cm. No other masses were identified. Approximately 3 weeks following the CT, a clinical whole-body FDGPET scan performed on the ECAT ART scanner showed multifocal bilateral FDG accumulation in the groin and pelvis. Also noted was bilateral curvilinear FDG uptake in the abdomen and pelvis consistent with
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Figure 1. Case 1 PET/CT scans, transverse view. The initial scan showed FDG elevation involving the mandibular ramus (A). A repeat scan conducted 4 months later demonstrated significant postsurgical changes with a focus of FDG uptake in the right neck, posterior to the surgical bed (B).
Figure 2. Case 2 PET/CT scans, transverse view. The initial PET/CT scan revealing elevated FDG accumulation in a jugulodigastric node (A). A follow-up PET/CT scan conducted 3 months later showed an increase in the intensity of FDG uptake in the same lymph node, indicating disease progression (B). FDG uptake in the floor of the mouth, shown here from the initial PET/CT scan (C), was deemed physiologic as it remained stable through the two scans and appeared to correspond to submental muscle.
Combined PET/CT in Oncology / Kluetz et al. 227
Figure 3. Case 3 PET/CT scans. In the sagittal view (A), focal FDG uptake was localized to the area of the C6 corpectomy site. The transverse view of the same PET/CT scan (magnified to area of interest) revealed involvement in the surgical site (B), as well as the left lamina of C6 with extension into the paraspinal muscle (C).
Figure 4. Case 4 PET/CT scan, transverse view. Following a full body PET scan that was equivocal for malignancy due to potential urinary excretion artifact, this PET/CT scan localized a focal area of increased FDG uptake to the region of the obturator lymph node chain, separate from and lateral to the ureter.
Figure 5. Case 5. The transverse view of the PET/CT scan shows focal areas of FDG uptake corresponding to adenopathy seen on the CT component (A). The coronal view of the full body clinical PET scan of this patient, conducted just prior to the PET/CT scan, was equivocal for adenopathy vs. benign ureteral excretion (B). This pattern of uptake was strikingly similar to the negative whole-body clinical PET scan of a man with benign prostatic hypertrophy (C).
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para-aortic and pelvic adenopathy. However, bilateral ureteral accumulation of tracer along the para-aortic region extending into the pelvis could not be excluded (Figure 5B). A PET/CT scan was acquired subsequent to the whole body PET scan (Figure 5A). The bilaterally symmetric abdomenopelvic uptake was clearly shown to correspond to para-aortic and illiac adenopathy with PET/CT.
Discussion The cases presented in this report demonstrate some of the benefits that may be realized by combined PET/CT imaging. By acquiring both images in the same session, the patient does not need to be moved from the scanning bed, thus eliminating changes in position that lead to misregistration of PET and CT images. This becomes particularly important for head and neck imaging, where changes in neck position have been shown to affect retrospective fusion of PET and MRI images and result in misalignment.20 In addition, near-simultaneous acquisition of the two scans eliminates the possibility of a new lesion seen on PET that has developed after the acquisition of the CT scan. Combined PET/CT scanning has proven to be useful at our center for the discrimination of physiologic from malignant FDG uptake. In the head and neck, FDG accumulation can be due to normal uptake in striated muscles such as the sternocleidomastoid.10 In addition, it has been shown that speaking during the uptake phase leads to accumulation in the laryngeal muscle.21,22 Even if the patient is instructed to limit speaking during the FDG uptake phase, lack of compliance, stress or anxiety often produce pronounced physiologic uptake that may confound PET interpretation. Bilateral, curvilinear FDG uptake supports benign muscle activity. However, malignant lymph node chains may produce similar patterns. The PET/CT scanner is able to accurately localize FDG uptake to masses outside of muscle planes, significantly enhancing the ability to discriminate between benign muscle uptake and malignancy. In cases 1 and 2, the patients presented with head and neck malignancies (Figures 1 and 2). In these cases, combined PET/CT localized the focal malignant FDG uptake to soft tissue masses outside of striated muscle planes. Additionally, case 2 demonstrates significant FDG accumulation in the floor of the mouth directly over submental muscle planes (Figure 2C). The fact that the FDG accumulation was bilateral and localized to the submental muscles, in addition to the stability of the FDG uptake in the follow up PET/CT scan while the lymph node and tongue lesions were progressing, supports the conclusion that the floor of the mouth finding is likely due to physiologic submental muscle uptake. With the added anatomic information provided by CT,
combined PET/CT may improve the specificity of FDGPET results in head and neck malignancies. While PET images of the head and neck can be confounded by physiologic muscle uptake, CT or MRI images of this region can also be difficult to interpret. Evaluation of head and neck cancer using CT or MRI alone can be challenging if significant post-surgical and/or post-radiation changes exist. In case 1, the patient had undergone resection before both PET/CT scans, distorting normal anatomy and making an analysis of CT or MRI difficult. In particular, the post-mandiblectomy scan in case 1 would have been difficult to evaluate for recurrence using a follow up CT scan alone (Figure 1B). By combining PET’s ability to discriminate post-surgical changes and radiation damage from disease with CT’s anatomic information to localize FDG uptake, interpretation of the combined images can be more accurate. Another area where normal physiologic uptake is a concern is the abdomen and pelvis. Here, excretion of FDG in the kidneys, ureters and bladder can be mistaken for tumor or can mask a nearby malignant lesion.11 Additionally, the normal bowel has been shown to demonstrate variable benign FDG accumulation.23–25 In cases 4 and 5, FDG uptake on a conventional wholebody PET scan alone was equivocal because of the proximity of the bladder and ureters to the lesion. However, with the anatomic data provided by PET/CT, malignant lesions were definitively confirmed. Case 4 demonstrates a focal area of FDG uptake immediately adjacent to the bladder, which was diagnosed as malignant pelvic adenopathy by PET/CT (Figure 4). In case 5, a conventional whole-body PET scan showed bilateral curvilinear FDG accumulation that was difficult to discriminate from ureteral excretion. Figure 5 demonstrates the similarity between the FDG uptake patterns seen in two conventional whole-body FDG PET scans: that of case 5, and the scan of a patient with benign ureteral excretion due to prostatic hypertrophy completed the same day. The side-by-side comparison of the two clinical PET scans (Figure 5B and 5C) is an example of the difficulty in discriminating malignancy from physiologic excretion in the abdomen. The combined PET/CT in case 5 correctly diagnosed bilateral adenopathy, easily discriminating tumor from physiologic ureteral activity (Figure 5A). In our experience, the use of PET/CT has had a significant impact on patient management. In particular, we have received excellent feedback from our surgical colleagues with respect to the utility of PET/CT scans. For example, in case 1, the first PET/CT scan identified the area of elevated FDG as involving the mandible (Figure 1A) but sparing the temporalis muscle and vascular bundle. By pinpointing the areas of involvement, the surgeon was better able to define margins and spare structures that were not affected by malignancy.
Combined PET/CT in Oncology / Kluetz et al. 229
In addition, the follow-up PET/CT study for this patient isolated a small residual lesion that was also surgically removed and found to be positive for tumor (Figure 1B). Due to the small size of the ulcerated lesion (1.5 cm 1.0 cm) and the significant post surgical changes in the area, this lesion may have been missed using CT follow up alone. In case 4, the PET/CT scan was also used effectively for surgical planning. In this case, laparatomy was successfully directed to the FDG focus in the left obturator lymph area. During the exploratory portion of the laparotomy the pelvis and abdomen were found to be negative for tumor and the surgeon may have ended the procedure at that point. However, due to the PET/CT results, the surgeon then proceeded directly to the left obturator lymph area and located and debulked the tumor. Another aspect of patient management where combined PET/CT can be beneficial is in evaluating response to therapy. Case 2 is an example of the use of PET/CT in therapeutic management. After the initial PET/CT scan helped to localize recurrence to the tongue base and left jugulodigastric node (Figure 2A), the patient was placed on a gene therapy protocol. The follow-up PET/CT scan administered 3 mo later showed an increase in intensity in the FDG uptake at the jugulodigastric node (Figure 2B) and tongue base. The finding indicated poor response to the therapy and the gene protocol was discontinued and an alternative treatment was sought. Case 3 is an example of the post-operative staging of a C6 lymphoma. Because the FDG uptake was isolated to the region of the surgical bed, a less aggressive form of chemotherapy was chosen. Additionally, accurate localization of the disease by PET/CT allowed the radiation port to be efficiently placed.
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Conclusion The cases illustrated in this review suggest that PET and CT images acquired in the same scanning session by a PET/CT scanner may improve both the accuracy and utility of PET image interpretation. In our experience, these accurately co-registered PET and CT images have helped to discriminate areas of physiologic uptake from malignant lesions in situations where conventional PET or CT alone was equivocal. In addition, the PET/CT scanner eliminates the co-registration of a PET scan with anatomic information from a CT or MRI that may have changed in the time between scans. Finally, precisely localized PET information can be used to plan surgical and medical therapy and in so doing, improve the management of patients with malignant disease.
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