Utility of Positron Emission Tomography (PET)

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1 11 : 1 Utility of Positron Emission Tomography (PET) in Medicine Summery The PET imaging is the recent advance in Nuclear Medicine which gives information at the molecular level. This helps in diagnosing, assessing the treatment response and recurrence in cases of malignancy. The hibernating viable myocardium is mapped for revascularization. It is the milestone in treating dementia and surgically the epilepsy and brain tumor. The X rays were invented in 1896 followed by invention of computed tomography by God Fray in 1960s. These investigations provide us the anatomical information. The PET scan concept was laid by David Kuhl and Roy Edwards in late 1950s. (1) The PET scan provides molecular imaging of biological function at the cellular level and eventually of the organ. This PET study is done with the Computed Tomography (CT) for attenuation correction of PET images and anatomical correlation. The most commonly used isotope is F 18 Fluorodeoxy glucose (FDG); a positron emitter that is analogous to the glucose molecule. It is transported from the plasma via facilitated transport with GLUT receptors and serves substrate for the phosphorylation by the enzyme hexokinase. Later it is trapped inside the cell as it is not the substrate for either phosphohexose isomerase or glucose-6- phosphatse (figure1). (2) The quantitative analysis of tumoral FDG uptake is calculated with Standardized Uptake Value (SUV). The differentiation of benign from malignant disease was tried with this SUV; however there are varied results seen with the use to differentiate inflammation from malignancy (SUV < 2.5 to 3 favours inflammation). It is predictive of grade of tumor(2,3) (Table 1). Table 1: Factors affecting FDG uptake: (3) Increased FDG uptake Decreased FDG uptake Higher tumor grade Benign lesion Large number of viable cells Necrosis Increased tumor blood flow Low grade or low cellularity, mucinous tumor Inflammation Hyperglycemia Tumor hypoxia High insulin Acute radiation Chronic radiation Acute chemotherapy Prior chemotherapy Recent surgery Scar GH Tilve, Shwetal Pawar, Sudeshna Maitra, Mumbai The various PET radiotracers available are Oxygen-15, Nitrogen-13, Rubidium-82 for myocardial perfusing studies. The isotopes are labeled to ligands for specific function as carbon-11 labeled to various drugs; Gallium-68 labeled to DOTATOC/DOTANOC for neuroendocrine tumor imaging; Fluorine-18 labeled to thymidine for studying the DNA function (cellular proliferation), Fluorine-18 labeled to misonidazole to study tumor hypoxia; Fluorine-18 labeled to estradiole to study estrogen receptor function etc (3,4). F 18 FDG PET scan in clinical practice The PET scan has indications in oncology, cardiology and neurology. The indications are also listed in table1. Cardiac viability study The mapping of myocardial damage i.e. the infracted but hibernating viable myocardium is done with the FDG PET scan. It is crucial to predict the post revascularization outcome in IHD. The FDG is taken up by the ischemic and infarcted but viable myocardium as the fatty acid metabolism changes to the glucose metabolism. The study can be done in the emergency setting after the myocardial infarction also. The myocardial viability assessment with FDG PET study is considered as gold standard. When the myocardial perfusion study at rest and FDG PET studies are compared; the mismatched areas on both the studies represent the areas of Normal cell glycolysis hexokinase Plasma glucose glucose glucose-6-phosphatase Glucose-6-phosphatase cancer cell glycolysis hexokinase Plasma FDG FDG FDG-6-phosphatase GLUT Glucose-6-phosphatase Fig. 1: Mechanism of uptake of FDG intracellularly

2 Medicine Update 2010 Vol. 20 a. b. Fig. 2 : a. Matched perfusion - metabolism suggesting nonviable myocardium, b. Mismatched perfusion metabolism suggesting viable myocardium. Fig. 3: Alzhiemer s dementia on FDG PET scan viable myocardium. The sensitivity is 86% to 93% and specificity of 93% to 99% and accuracy of 93% on various studies. (5-9) Assessment of brain disorders The mapping of cerebral metabolism is done with the FDG PET scan. The interictal FDG PET study is done to locate the hypometabolic areas with maximum sensitivity and specificity of 84% and 86% respectively in temporal lobe epilepsy. The Alzheimer s dementia (fronto-parietal hypometabolism) (figure 3) can be diagnosed at the early stages when the MRI can be negative. The degree of hypometabolism on PET correlates with the rate of cognitive decline. The differentiation from the other types of dementias can be done. The Picks disease (frontotemporal hypometabolism), vascular or multiinfarct dementias can be differentiated from Alzheimer s disease. (2) The brain tumors show high uptake depending on the grade of tumor. The FDG PET scan can differentiate between the tumor recurrence verses radiation necrosis which is difficult to diagnose on MRI. The low grade gliomas have low sensitivity on PET scan. The PET scan can differentiate lymphoma and toxoplasmosis Fig. 4: FDG PET scan in lymphoma- mediastinal involvement. especially in the AIDS patients. (1) the movement disorders are assessed with 2-carbomethyoxy-3-(4-chlorophenyl)-8-(2-18 F-fluoroethyl) nortropane (F18-FECNT) and F-DOPA; both allow assessment of integrity of presynaptic dopaminergic neurons. 11C Cacloprode PWT provides an indirect marker of changes in the levels of dopamine in the synaptic cleft.(10-12) Oncology Lymphoma The PET scan has shown challenging results in the evaluation of lymphoma as compared to Gallium scan. The accuracy of FDG PET scan is about 96% with sensitivity of >91% in detection of lymphoma lesion as compared to 56% of CT scan. It can be used at different levels such as initial staging, assessment of response to therapy and restaging or recurrence. It is more accurate in assessing extranodal disease including bone marrow and spleen. The sensitivity is found to be low in low grade lymphomas.(2,3,14) Lung cancer The PET scan shows excellent results in the non-small cell tumor of lung. The characterization of solitary pulmonary nodule was 646

3 Utility of Positron Emission Tomography (PET) in Medicine Table: 2 The FDA approved indications of the FDG PET/CT scan: (3,13) Sr no. Clinical condition Indication 1 Solitary pulmonary nodule Characterization 2 Lung cancer (non-small cell) Initial staging 3 Lung cancer (non-small cell) Diagnosis, staging, restaging 4 Esophageal cancer Diagnosis, staging, restaging 5 Colorectal cancer Locating tumors if rising CEA suggest recurrence 6 Colorectal cancer Diagnosis, staging, restaging 7 Lymphoma Diagnosis, staging (only when used as an alternative to gallium scan) 8 Lymphoma Diagnosis, staging, restaging 9 Melanoma Evaluate recurrence prior to surgery instead of gallium scan 10 Melanoma Diagnosis, staging, restaging (evaluating regional nodes not covered) 11 Breast cancer Staging when distant metastases, restaging locoregional recurrence of metastasis, monitoring treatment response for locally advanced and metastatic cancer when change in therapy is anticipated 12 Head and neck cancers (excluding Diagnosis, staging, restaging central nervous system and thyroid) 13 Thyroid cancer Restaging recurrent or residual cancers of follicular cell origin that were previously treated by thyroidectomy and radioiodine ablation with serum thyroglobulin >10 ng/ml and negative I-131 whole body scan. 14 Cervical cancer Possible detection of residual cancers or recurrent tumor after therapy 15 Ovarian cancer Initial staging, detecting recurrence, detecting recurrence when CA-125 titre is rising but computed tomography is negative 16 Pancreatic cancer Possibly differentiating benign form malignant, detect metastases 17 Small cell lung cancer Initial staging, restaging, diagnosis of occult tumor in paraneoplastic syndrome 18 Testicular cancer (pure seminoma or nonseminomatous germ cell) Initial staging, evaluate residual mass, recurrence when computed tomography is normal but serum factors rising 19 Myocardial Viability SPECT 20 Myocardial Viability Primary or initial diagnosis, or following an inconclusive SPECT prior to revascularization. SPET may not be used following an inconclusive PET scan 21 Perfusion of the heart using Rubidium Noninvasive imaging of the perfusion of the heart 82* Tracer 22 Perfusion of the heart using ammonia Noninvasive imaging of the perfusion of the heart N-13* tracer 23 Refractory Seizures Pre-surgical evaluation only 24 Dementia. The differential diagnosis of frontotemporal dementia and Alzheimer s disease under specific conditions tried first in lung cancer to differentiate from inflammation from malignancy. The results were variable. The differentiation form tuberculosis is difficult as the infective lesion also shows similar FDG uptake pattern. However the negative predictive value is >90% to avoid unnecessary biopsy. (2,3) The non-small cell lung cancer shows sensitivity of 75% to 91% in nodal metastases with higher specificity for bone, adrenal and distant metastases. The response to chemotherapy and recurrence can also be evaluated. (15) Head and Neck cancers Fig. 5 : Ca lung with liver metastasis. The PET can diagnose unknown primary in 20-50% patients of head and neck cancer. The sensitivity of PET scan is 79-96% in post radiation restaging to look for recurrence where the anatomy is distorted. It is particularly useful to evaluate the postoperative patients also. The thyroid cancers with undifferentiated variety, medullary carcinoma of thyroid show FDG uptake. The dedifferentiated carcinoma of thyroid that is non-iodine concentrating can be evaluated on PET scan and show poor 647

4 Medicine Update 2010 Vol. 20 prognosis(2,3,10,16). Gastrointestinal tumors The PET scan has overall sensitivity of 95% in oesophageal cancer. However has no advantage over endoscopic ultrasonography in detecting the extent of primary disease. However the sensitivity for detection of nodal and distant metastases is high. It is also useful to detect the response to chemotherapy and recurrence of disease. The sensitivity of PET scan is high in all types of colorectal and gastrointestinal malignancies except mucionus variety. The sensitivity is about 92% in tumor, nodal and distant metastases. The PET scan can be used in staging, Post-operative residual disease, recurrence with rising CEA levels, post radiofrequency ablation evaluation of liver lesions.(2,3,10,17) The pancreatic nodules can be differentiated between benign and malignant disease. The cholangiocarcinomas and gall bladder tumors can be studied for local and distant spread. Melanoma The thickness of primary lesion is most important in melanoma. The FDG PET scan has no significant role in detection of primary disease. The sentinel node detection is better than PET scan for nodal metastases. However the PET scan stands above all in detection of distant metastases and recurrence of disease (2,3,10,14). Breast cancer The sensitivity of PET scan is 88% in primary lesion >2cm. The nodal and distant metastases evaluation sensitivity ranges form %. The uptake value suggests the aggressiveness of the disease. The F-18 labeled estradiole is used as receptor specific imaging in breast cancer(2,3,10,18-21). Ovarian cancer It is used for staging and restaging of cancer; especially with Table 3 : Timing of FDG PET scan in clinical scenario (2) Sr no. History Action 1. Prior surgery Delay scan 4-6 weeks post-operatively 2. Chemotherapy Delay scan several weeks or schedule before next cycle 3. Radiation therapy Delay scan at least 3 moths after completion of radiotherapy 4. Colony stimulating factor (G-CSF) 5. Diabetes Mellitus Serum glucose (fasting) >150 Delay scan for short acting agents or several weeks for long acting agents Reschedule scan after control of fasting blood sugar 6. Breastfeeding Discontinue breast feeding for 6 hrs 7. Pregnancy Contraindicated- avoid the radiation hazards elevated Ca-125. CA 19-9, Alpha fetoprotein and HCG. The mucinous variety of ovarian cancer shows low sensitivity on PET scan(2,3,10,22). Cervical cancer The local invasion with recurrence can be studies on PET scan. The radiotherapy planning is also done to avoid radiation to the normal structure around the tumor(2,10,22). Testicular cancer The seminomatous type of tumor shows high sensitivity and specificity on FDG PET scan. The initial staging and recurrence can be studied (2,10,22). Musculoskeletal system: The differentiation of benign from the malignant bone tumors is difficult on PET scan as the giant cell tumor, fibrous dysplasias and eosinophilic granulomas also show FDG uptake. The low grade soft tissue sarcomas also are less FDG avid. However PET can detect the metabolic rates, guiding biopsy, residual tissue after surgery and recurrence in the stump and also planning of radiation therapy.(10) Radiotherapy planning on FDG PET Scan Grisburg et al performed radiotherapy planning for cervical cancer patients. (23) The radiation dose to the normal tissue surrounding the tumor mass and necrotic areas is avoided. The intensity modulated therapy is planned. Such planning of radiation therapy is also done for carcinoma lung, brain, head and neck and lymphoma. Newer areas of research The role of PET scan in the inflammation and infection is been studied. The use in the infections such as pyrexia of unknown origin is been studied to locate the sites of active infection as the macrophages and activated lymphocytes show increased FDG concentration. Table 4 : Tumors with low FDG uptake (2) Sr no Tumors with low F-18 FDG PET uptake 1 Prostate cancer 2 Renal cell carcinoma 3 Bronchoalveolar cell lung cancer 4 Mucinous adenocarcinoma 5 Carcinoid 6 Low grade sarcomas 7 Low grade lymphomas - MALT mucosa- associated lymphoma Small cell lymphocytic non-hodgkin lymphoma 8 Differentialted thyroid cancer (iodine-avid) 9 Hepatocelluar carcinoma 10 Metastases to brain 648

5 Utility of Positron Emission Tomography (PET) in Medicine The arteritis like Takayasu Arteritis also shows FDG concentration. The diagnosis and therapy response in this arteritis is also studied and as compared to the Magnetic resonance imaging angiography; the sites metabolic activeness was better studied with FDG PET scan. The tuberculosis shows very high uptake of FDG and behaves like malignant tissue. So the FDG PET scan has no proven role in the diagnosis or differentiation from malignancy. However it can play crucial role in defining the disease extension, multiple sites and evaluation of response to anti-tubercular drug therapy. The role of PET scan in assessment of diabetic foot, infected joints, implants, pace makers has been studied. However these indications have shown varied FDG concentration pattern and is under further characterization (24-28). The future of PET scan lies in the use of tumor specific marker agents to study the tumor and patient specific approach. The use of FDG PET scan in non-oncological conditions is the challenge. References 1. Jaffe Carl C. Medical Imaging and Visual Psychology Medical Radiography and Photography, Volume 1984: Eugene C. Lin, Abass Alavi, PETand PET/CT a clinical guide;2005: Ziessman Harvey, O Malley, Thrall J, The requisites Nuclear Medicine, 2006: 3 rd edition: Been LB, Suurmeijer, Cobbn DC. Et al: F-18 FLT-PET in oncology: current status and opportunities. Eur J Nucl Med 31: , Machac J, Cardiac Positron Emission Tomography Imaging: Seminars in Nucl Med, 35:17-36, Wahl RL: Principles and Practice of positron Emission Tomography. Baltimore, Lippincott Williams & Wilkins, Tillisch J, Brunken R, Marshall R, et al. Reversibility of cardiac wall-motion abnormalities predicted by positron tomography. N Engl J Med. 1986; 314(14): Tamaki N, Kawamoto M, Tadamura E, et al. Prediction of reversible ischemia after revascularization. Perfusion and metabolic studies with positron emission tomography. Circulation. 1995; 91(6): Pasquet A, Robert A, D Hondt AM, et al. prognostic value of myocardial ischemia and viability in patients with chronic left ventricular dysfunction. Circulation. 1999; 100(2): Pant G. S. Kumar Rakesh, advances in diagnostic medical physics. 2006: Davis MR, Votaw JR, Initial human PET imaging studies with the dopamine transporter ligand 18F_FECNT. J Nucl. Med. 2003;44(6): Otsuka M, Ichiya Y, Luwabara T et al. Differences in the reduced 18F- DOPA uptakes of the caudate and putamen in Parkinson s disease : corrlations with the three main symptoms. J Neurol Sci. 1996; 136(1-2): Manual System, Pub , Medicare national Coverage Determinations Manual, Chapter 1, part 4, Section Macapinlac HA: FDG PET and PET/CT imaging in lymphoma and melanoma. Cancer J 10: , Vesselle H, Pugsley JM, Vallieres E, et al: The impact of FDG F-18 poairton emission tomography on the surgical staging of non-small cell lung cancer. J Thorac Cardiovasc Surg 124: , Kubota K, Yokoyama J, Yamagichi K, et al: FDG-PET delayed imaging for the detection of head and neck cancer recurrence after radio-chemotherapy: comparison with MRI/CT. Eur J Nucl Med 31: , Delbeke D, Martin WH: PET and PET-CT for the evaluation of colorectal carcinoma. Semin Nucl Med 34: , Eubank WB, Mankoff DA: Evolving role of positron emission tomography in breast cancer imaging. Semin Nucl Med 35:84-95, Kumar R, Alavi A. FDG-PET in the management of breast cancer. Radiol Clin North Am. 2004;42: Kumar R, Chuhan A, Zhuang H. et al. FDG-PET positive lymph nodes are highly predictive of metastases in breast cancer. Nucl Med Commun. 2006;27(3): Schelling M, Avril N, Nahrig J, et al. PET using FDG for monitoring primary chemotherapy in metastastic breast cancer patients. J Clin Oncol. 2000;18: Kumar R, Alavi A: PET imaging in gynecological malignancies. Radiol Clin North Am 42: , Grisburg PW, Mutch DG. Treatment planning guidelines in patients with cervical cancer and negative lymph nodes by FDG-PET, Int Radiation oncology Biological Physics. 2005;58: Ghasan Sl-Haddad, Hongming Z, Gupta N, et al. Evolving role of PET in the management of patients with inflammatory and benign disorders. Semin In Nucl Med 34: , Zhuang H, Alavi A. F-18 FDG PET imaging in the detection and monitoring of infection and inflammation. Semin in Nucl Med. 2002; 32: Meller J, Sahlmann CO, Scheel AK: FDG PET in fever of unknown origin. J Nucl Med. 2007; 48: Blockmans D, Utility of imaging in assessment of vascular inflammation. Cleveland Clinic J of Med SII-95 69: Yago Y, Yukihiro M, Kuroki, et al. Cold tuberculosis abscess identified by FDG PET. Annals of Nucl Med. 19 (6): ;