INTRODUCTION
The main objectives of imaging in oncology are lesion detection, lesion characterization, evaluation of the extent of the tumor and staging, assessment of the therapeutic response and restaging of malignant disease. Conventional imaging modalities like ultrasonography (USG), Computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used in the management of cancer patients. During the past decade, the application of positron-emission tomography (PET) has remarkably improved the management of various oncological, neurological and infectious diseases. Conventional imaging rely on the anatomical changes whereas, PET being a functional technique allows diagnosis of pathological processes at a very early phase when changes are still at the molecular level. PET, however, is limited in its ability to provide information on the exact location of lesions with abnormal uptake because of the absence of precise anatomic landmarks. A new imaging technique combining state-of-the-art PET and CT equipment (integrated PET-CT) has been introduced in clinical use. This PET-CT device acquires both PET and CT images, which are contemporaneous and co-registered by means of hardware arrangement to localize abnormal uptake on PET with improved accuracy. PET and PET-CT have a very high sensitivity and a high negative predictive value for lesion detection as compared to conventional morphological modalities like CT. In addition to qualitative image display, it is possible to quantify specific uptake value normalized to the injected dose which is called “standardized uptake value” (SUV). The SUV provides an approximate indicator that correlates with metabolism depicted by the PET radiotracer in the tissue of interest.
The clinical value of PET and PET-CT for the diagnosis, initial staging, monitoring the response to chemotherapy and determination of metastatic disease in patients with various cancer has been well established. It has shown to change management of cancer patients significantly. However, role of PET and PET-CT in various retinal diseases has not been fully explored. There is very limited literature in this regard. In this chapter we will discuss basic principles of this technique, mechanism of radiotracer uptake, patient preparation and its possible clinical applications.
PRINCIPLE AND TECHNIQUE
PET imaging utilizes beta-emitting radionuclides such as 11C, 13N, 15O and 18F, which decay by positron emission. After being emitted from the nucleus, a positron will combine with a nearby electron through a process known as annihilation. Annihilation converts the mass of both particles into energy in the form of two anti-parallel 511 keV gamma rays. The PET detectors are arranged in a ring in order to detect these gamma rays.
MECHANISM OF FDG
2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) which is the glucose analogue is the most widely used radiotracer in clinical practice. Other radiotracers like 18F-fluorothymidine, 11C-choline, 11C-methionine etc. are still under process of development and are not commonly used. 18F-FDG is able to detect altered glucose metabolism in various oncological, neurological and inflammatory diseases processes. Like glucose, 18F-FDG is transported into cells by means of a glucose transporter protein and begins to follow the glycolytic pathway. Once inside the cell,18F-FDG is phosphorylated into 18F-FDG-6-phosphate. However18F-FDG-6-phosphate cannot continue through glycolysis as it is not a substrate for glucose-6-phosphate isomerise enzyme. As a result, 18F-FDG-6-phosphate is biochemically trapped within the cell. This process of metabolic trapping constitutes the basis of PET imaging.
PATIENT PREPARATION
All patients should be fasted for a minimum of 4 hours before the study, and blood glucose level should be less than 150 mg/dl. Normal blood glucose level is very important in diabetic patients as increased glucose level can alter distribution of 18F-FDG which can lead to false negative results. 18F-FDG is administered in dose of 5.2 MBq (0.14 mCi)/kg through a peripheral vein. Patients are asked to refrain from talking, walking and any other muscular activity after FDG injection otherwise there will be non-specific FDG uptake in skeletal muscles. Sequential overlapping emission scans of the neck, chest, abdomen, and pelvis should be acquired on PET or PET-CT scanner 60-minutes after injection of radio tracer. Most of the time no contrast is used for the CT portion of the PET-CT study; therefore no additional patient 3preparation is required. However, if contrast is used for PET-CT study, the precautions normally taken for contrast CT should be observed. Till now most of PET-CT procedures are performed as non-contrast CT which is used for better localization of lesions only. However, recently more and more stress is being given to perform proper contrast CT along with PET in the same setting when patient is going for PET-CT examination.
NORMAL DISTRIBUTION OF FDG
Since brain uses glucose as a substrate for most of its energy, there is intense FDG uptake in the brain. Skeletal muscle is another common site of physiological uptake, which is increased by both voluntary and involuntary muscle activity. Muscle uptake is generally symmetrical but sometimes can be asymmetrical, especially in torticollis and unilateral paralysis. Uptake in the gastrointestinal tract is variable and is mainly due to smooth muscle activity associated with peristalsis, bacterial uptake and in metabolically active mucosa. Unlike glucose, FDG is not totally reabsorbed in the kidneys and FDG activity is seen in the urinary tract. However, with the PET-CT, uptake in muscles and brown fat rarely poses interpretation problems.
CLINICAL APPLICATIONS
PET scanning is considered to be useful for the following indications: (a) initial diagnosis and distinction of benign from malignant neoplasms; (b) staging of the malignancy; (c) determination of the response to therapy; and (d) restaging: detection of regional and distant metastasis, distinguishing scar from residual neoplasm.
Choroidal Melanoma
Early diagnosis and correct staging remains mainstay of better outcome in most oncological patients and choroidal melanoma is not an exception. PET and PET-CT plays an important role in staging, restaging and evaluation of treatment response in patients with malignant melanoma. There is limited data in regard to initial diagnosis and staging of choroidal melanoma. SUVs have been found to correlate well with tumor differentiation. Well differentiated tumors show lower SUVs as compared to poorly differentiated tumors which show higher SUVs. The sensitivity of PET-CT is much better as compared to conventional imaging modalities like CT and MRI. The diagnostic criteria of CT and MRI for lymph nodes metastases is based on the size of lymph nodes. Any lymph node more than 1 cm is considered as pathological while lymph node less than 1 cm considered as normal. However, the diagnostic criterion of PET-CT is based on metabolism of lesion and not the size. Therefore, PET-CT is likely to be more accurate than conventional imaging modalities like CT and MRI. However, PET-CT has limited value in early diagnosis of T1 tumors. This is because of limited resolution (5 mm) of PET-CT. PET-CT needs certain number of tumor cells with increased glucose metabolism which can be seen by PET-CT. Therefore, PET-CT has been found to have lower detection ability of small size tumors and tumor with low tumor burden.
Reddy et al evaluated the minimum size of untreated choroidal melanomas that can be determined by the PET-CT. In this study of 50 consecutive patients who underwent whole body PET-CT, author compared PET-CT results with clinical measurements derived from ophthalmoscopic, angiographic, and ultrasonographic imaging. The lesions having SUV of more than 2.5 were considered positive. Among the 50 patients, PET-CT scan was positive in 14 (28%) tumors. PET-CT was false negative in all small choroidal (T1) tumors. PET-CT identified 33.3% of T2 melanomas, and 75% of T3 melanomas. The smallest tumor which was detected by PET-CT had basal dimensions of 3 × 5.9 and an apical height of 2.9 mm. The authors concluded that PET-CT is capable of identifying certain medium (T2) and most large sized (T3) choroidal melanomas and physiological imaging was not completely dependent upon tumor size.
Finger et al recently correlated the clinical, ultrasound and pathological features of the eyes first evaluated by FDG PET-CT and then enucleated for choroidal melanoma in 14 consecutive patients. Ultrasound was used to measure the tumor size and evaluate the tumor shape and intrinsic vascularity. Of the 14 tumors, 13 were T3 and one was T2. The mean tumor height was 10.6 mm (range 3.5–17.7) with a largest basal dimension of 19.3 mm (range 14.5–30). Patients having melanoma with SUV e•4.0 had larger basal dimensions and were epithelioid-cell type. Patients with the two highest SUV tumors died due to metastatic melanoma. Increased SUVs noted on PET-CT were positively correlated with known clinical, pathological and ultrasound features linked to metastatic potential of choroidal melanoma. In 4another study, the same group of clinicians investigated the value of whole body PET-CT in screening for metastatic choroidal melanoma in 52 patients initially diagnosed with choroidal melanoma. PET-CT scans were used as a screening tool at the time of their initial diagnosis. The standards for reference were further imaging and/or subsequent biopsies. Two of 52 (3.8%) patients were found to have metastatic melanoma before treatment. One patient had involvement of multiple sites. The most common sites for metastases were the liver, bone, and lymph nodes. Brain involvement was also present in one patient. PET-CT showed false positive results in three patients (5.7%) when further evaluated by histopathology and/or additional imaging. In seven patients (13.4%) PET-CT imaging detected benign lesions in the bone, lung, lymph nodes, colon, and rectum. The authors concluded that PET-CT imaging can be used as a screening tool for the detection and localization of metastatic choroidal melanoma. Liver enzyme assays did not identify liver metastases, while PET-CT revealed both hepatic and extra-hepatic metastatic melanoma. PET-CT imaging may improve upon the conventional methods of screening for detection of metastatic disease in patients initially diagnosed with choroidal melanoma.
PET-CT also plays an important role in restaging in patients with choroidal melanoma. Since PET-CT is done as whole body imaging and functional in nature, it is expected to show more metastatic lesions as compared to CT MRI. PET-CT scan not only detect lymph nodes, soft tissue and organ metastases but also detects bone metastases with high accuracy. However, due to high physiological FDG uptake in brain, PET-CT has limited diagnostic value in detecting brain metastasis. Kurli et al evaluated role of PET-CT in staging of patients with metastatic choroidal melanoma. Subsequent biopsies were performed to confirm the presence of metastatic disease. Twenty patients underwent PET-CT for suspected metastatic choroidal melanoma. Eighteen were imaged because of abnormal clinical, hematologic, or radiographic screening studies during the course of their follow-up after plaque brachytherapy or enucleation. Two were imaged before treatment of their primary tumor. PET-CT revealed or confirmed metastatic melanoma in eight (40%) of these 20 patients. The mean time from initial diagnosis to metastasis was 47 months (range 0 to 154). The most common sites for metastases were the liver (100%), bone (50%), lung (25%), lymph nodes (25%), and subcutaneous tissue (25%). Cardiac, brain, thyroid, and posterior abdominal wall lesions (12.5%) were also noted. Six patients (75%) had multiple organ involvement. No false positives were noted. PET-CT imaging also detected benign lesions of the bone and lymph nodes in three patients. All patients had hepatic metastases and liver enzyme assays were abnormal in only one (12.5%) of eight patients. The authors concluded that PET-CT is a sensitive tool for the detection and localization of metastatic choroidal melanoma.
Intraocular Metastasis
Choroidal metastases are the most common intraocular malignancy and are the first sign of systemic malignancy in approximately one-third of patients. Of patients with no previous diagnosis of cancer, oncological evaluation fails to find the primary lesion in approximately half of the cases (Figures 1.1A to D). Ultrasonography, CT and MRI are initial diagnostic modalities used for this purpose. However, these modalities have many limitations and lower accuracy in detecting primary site. PET-CT may improve the yield of the systemic work-up. Combined PET-CT is a useful addition to the work-up of patients with choroidal metastases. It provides the opportunity to detect lesions not visible with other imaging modalities and the ability to image patients with contraindications to magnetic resonance imaging.
Ocular Adnexal Disease
PET-CT has been found to play an important role in evaluation of lymphoproliferative ocular adnexal disease. It has been used for initial staging, evaluating therapy response and restaging. PET has high sensitivity and specificity for initial staging and restaging after treatment in patients with high grade lymphoma. Valenzuela et al, evaluated the role of FDG-PET in the initial staging of 11 patients with ocular adnexal lymphoma (OAL). PET found distant disease in 5 of 6 lymphoma patients with systemic disease; 4 of these patients (66%) were upstaged, changing the clinical management. Orbital lesions were demonstrated in 3 of 11 patients, giving PET a sensitivity of 27% in the orbit and 83% systemically for detection of lymphoma. The authors concluded that FDG-PET has ability to find systemic extranodal lymphomatous sites not detected with CT/MRI, which may result in important changes in staging and management.5
FIGURES 1.1A TO D: A 64-year old female presented with diminished vision left eye. Clinical and radiologically diagnosed to have optic nerve melanoma underwent whole body PET-CT for staging. NCCT orbit demonstrates a hyperdense choroidal mass (arrow head) A. PET-CT scan shows mildly increased FDG uptake (SUV 1.5) in the mass seen on the CT (arrow head) B. NCCT chest demonstrates circumferential thickening of mid esophagus leading to obstruction (arrow) C. PET-CT scan shows intense increased FDG uptake (SUV 8) in the esophageal lesion seen on the CT (arrow) D. These findings are suggestive of primary carcinoma of esophagus with choroidal metastasis.
Limitations
Active granulomatous infections like tuberculosis, sarcoidosis, can be metabolically active and can lead to false positive results. Recent studies have shown better results with delayed PET images taken several hours after FDG injection (dual time point imaging), along with routine one-hour imaging protocol. These studies concluded that malignant lesions show increased FDG uptake over the time, while benign lesions have a declining pattern of uptake with time. Low-grade tumors may not appear abnormally ‘hot’ on dedicated PET/ PET-CT scans due to significantly lower SUVs. PET and PET-CT cannot detect micrometastases and very small lesions as these lesions show lower SUVs due to partial volume effect.
Infectious Diseases
FDG is a marker of glucose metabolism and is not specific for malignant lesions. Any process which leads 6to increased glucose metabolism can be detected with FDG-PET. Soon after the introduction of FDG-PET for human studies, it was noted that lesions with substantial inflammatory cells also appears positive on FDG-PET. Benign processes such as infection, inflammation and granulomatous diseases appear to have increased glycolysis and are therefore readily visualized by FDG-PET imaging. High tissue radioactivity after administration of 18F-FDG corresponds to increased glucose uptake and consumption through the hexose monophosphate shunt, the main source of energy in chemotaxis and phagocytosis. Activation of phagocytes, also known as respiratory burst activation, leads to increased 18F-FDG uptake. High degree of 18F-FDG uptake is seen in neutrophils during acute phase of inflammation, while macrophages and polymorphonuclear leukocytes take up FDG during chronic phase.
Granulomatous Disease
India has a high prevalence of granulomatous diseases like tuberculosis and sarcoidosis. Unfortunately, FDG PET does not behave in any characteristic manner in these conditions and shows variable FDG uptake according to the grade of inflammatory activity (Figures 1.2A to D). However, biopsy and histopathological examination may be essential for final diagnosis. FDG-PET can play a role in evaluating the extent of the disease, in guiding biopsy from metabolically active lesions and in follow up of these patients for treatment response. In addition, we also feel that PET-CT can be useful for detecting suspected recurrences and residual disease activity in patients treated previously.
FIGURES 1.2A AND D: A 45-year old presented with diminished vision left eye. Clinical and radiologically diagnosed to have optic nerve melanoma underwent whole body PET-CT for staging. NCCT orbit demonstrates a hyperdense choroidal mass (A). PET scan shows mildly increased FDG uptake (SUV 2.2) in the mass seen on the CT (B). PET-CT scan shows mildly increased FDG uptake in the mass seen on the CT (C). Whole body FDG-PET scan shows focal areas of increased FDG uptake (SUV 2.8) in multiple mediastinal and supraclavicular lymph nodes (D). These findings are suggestive of infective granulomatous pathology with extensive involvement of choroid, mediastinal and supraclavicular lymph nodes.
SUMMARY
Combined PET/CT is a useful addition to the work-up of patients with choroidal masses such as metastases. PET-CT not only evaluates primary tumor but also provides the opportunity to detect distant metastases not visible with other imaging modalities. In addition it has the ability to image patients with contraindications to magnetic resonance imaging.
BIBLIOGRAPHY
- Donaldson MJ, Pulido JS, Mullan BP, Inwards DJ, Cantrill H, Johnson MR, Han MK. Combined positron emission tomography/computed tomography for evaluation of presumed choroidal metastases. Clin Experiment Ophthalmol 2006; 34(9):846–51.
- Finger PT, Chin K, Iacob CE.18-Fluorine-labelled 2-deoxy-2-fluoro-D-glucose positron emission tomography/computed tomography standardised uptake values: a non-invasive biomarker for the risk of metastasis from choroidal melanoma. Br J Ophthalmol 2006; 90(10):1263–6.
- Kurli M, Reddy S, Tena LB, Pavlick AC, Finger PT. Whole body positron emission tomography/computed tomography staging of metastatic choroidal melanoma. Am J Ophthalmol 2005; 140(2):193–9.
- Reddy S, Kurli M, Tena LB, Finger PT. PET/CT imaging: detection of choroidal melanoma. Br J Ophthalmol 2005; 89(10):1265–9.