Physical Properties

In positron radioactive decay, a positron ( β ⁺ ) ejected from the atom travels a short distance before meeting a negative particle (electron) and undergoing annihilation. The resulting two 511-keV photons travel at 180 degrees from each other. These high-energy photons do not interact well with routine gamma cameras but are optimally detected by the specialized ring of detectors in a PET camera. Photons received within a short enough time interval at opposing detectors are registered as “coincidence photons,” or those originating from the same decay event. The result is a superior image to those achieved with gamma camera single-photon studies (e.g., with technetium-99m–labeled agents).

Many PET-emitting isotopes have very short half-lives (T _1/2 ), requiring a cyclotron to be in extremely close proximity. The 109.7-minute T _1/2 of F-18 means it can be shipped from local and even regional production facilities. On the other hand, the T _1/2 is not excessively long, and radiation exposure is lower than many agents with longer-lived radiolabels. Dosimetry information is outlined in Appendix 1 .

Kinetics and Distribution

In malignant cells, increased expression of membrane glucose transporters (e.g., glut-1) results in higher levels of intracellular glucose. Within these cells, the levels of hexokinase (hexokinase II) activity are also increased, phosphorylating glucose, which then moves through the glycolysis pathway. F-18 FDG is taken into the cell and phosphorylated by the same mechanisms as glucose, but F-18 FDG cannot be metabolized further ( Fig. 12.1 ). In addition, due to the lower levels of glucose-6-phosphatase in cancer cells, FDG remains effectively trapped because phosphorylated FDG cannot diffuse back across the membrane. The normal distribution of F-18 FDG is shown in Figs. 12.2 and 12.3 .

Glucose and F-18 fluorodeoxyglucose (FDG) intracellular kinetics. F-18 FDG uses the same uptake and phosphorylation pathways as glucose, although it cannot be metabolized further through glycolysis. In cancer cells, radiotracer accumulation is increased because of different levels of enzymatic activity. G-6-P, Glucose-6-phosphatase.

Normal distribution of F-18 fluorodeoxyglucose (FDG). Uptake is normally intense in the brain and urinary tract, moderately intense in the liver, and variable in muscles (especially of the oropharynx), heart, and bowel.

Normal variants. (A) Marked uptake can be seen normally in the small and large bowel. In some cases, the increased bowel activity is related to metformin use. (B) Axial positron emission tomography (PET) and corresponding computed tomography (CT) images show uptake in the oropharynx. Normal activity is typically symmetrical and may be intense when patients swallow or talk. L, Lingual tonsil; M, mandible; Mx, maxilla; P, parotid gland; PT, palatine tonsils; S, submandibular gland.

Patient Preparation

Because glucose competes with F-18 FDG for uptake, the patient’s glucose level should be checked before injection. The upper-limit cutoff varies among institutions, but a value under 200 mg/dL is generally considered acceptable.

Insulin, whether endogenously released in response to a meal or following administration to diabetics, stimulates the glucose transporters (e.g., glut-1), which are highly expressed in muscle cell membranes. This dramatically increases muscle uptake ( Fig. 12.4 ), thereby potentially decreasing uptake in tumor. To minimize the impact, patients fast overnight or for at least 4 to 6 hours before injection and avoid carbohydrates in the meal (or even the day) before injection. Patients with diabetes should not be given short-acting insulin within 2 hours of radiotracer injection, and long-acting insulin should be held overnight. The scan must be carefully scheduled because it may be difficult to coordinate with the diabetic patient’s serum glucose levels, which can fluctuate widely over the course of the day. When this is the case, optimal times often include early morning, before eating or taking insulin, and early afternoon, with the patient fasting after eating a light early breakfast and taking the morning short-acting insulin dose. For non–insulin-dependent diabetics taking the medication metformin, consideration should be given to withholding it for 1 to 2 days because metformin has been shown to dramatically increase uptake in the bowel.

(A) Elevated muscle activity can occur from increased insulin levels (i.e., injected insulin in a diabetic and postprandial secretion in nondiabetics) activating membrane glut-transporters. (B) Strenuous exercise can also alter distribution. When muscle activity is extensive, scans may need to be repeated after adequate preparation because it can result in diminished activity in lesions.

Muscle activity is also minimized by limiting vigorous exercise for 1 to 2 days before the examination, and sedatives (e.g., alprazolam oral 0.5 mg) are routinely administered for patients with head and neck cancer who have undergone surgery in the past, helping to prevent frequently problematic increased background muscle activity.

Dose Administration and Uptake

Administered doses of F-18 FDG have been steadily decreased over the years. With the introduction of improved camera technology, such as time-of-flight (TOF) detection, typical doses are on the order of 7 to 8 mCi (259–296 MBq), up to half that used with the previous-generation scanners.

Patients should remain completely still and quiet for the uptake period, which is usually 50 to 65 minutes to achieve the optimum target-to-background ratio balanced with the physical decay T _1/2 . Some studies have suggested that additional delayed images at 90 to 120 minutes may improve sensitivity and specificity because tumors tend to continue accumulating F-18 FDG while activity continues to decrease from other tissues and benign processes. In the case of astrocytomas, which are especially difficult to image with F-18 FDG, an even greater interval (on the order of hours) may increase the accuracy. However, prolonged waiting periods are not generally practical in the clinic. Whatever delay is used, subsequent studies should be performed in a consistent manner to be certain that the changes seen are not artificially created.

PET/CT Scan Acquisition

Patients are usually imaged in the supine position after bladder voiding. Because CT artifact occurs when the arms are in the field of view, they are most often placed above the head when the pathology is in the chest, abdomen, and pelvis but left at the patient’s side when the tumor is in the head and neck.

The study is acquired in two phases. First, a transmission scan is performed using an external radiation source for attenuation correction. Originally, radiation sources (e.g., germanium-68 or cesium-137 rods) rotated around the patient, requiring several minutes. CT radiography, on the other hand, requires only seconds to cover the entire body. Based on the interactions of the x-ray photons with tissues, an attenuation-correction map is built and applied to the photons detected from the patient during the second phase of imaging, the emission PET scan. Attenuation correction allows PET data to be displayed with the proper intensity and is necessary for quantification of activity. The emission scan is acquired as a series of partially overlapping blocks of data, or bed positions, as the patient is moved through the camera. The scan time for each bed position can be modified depending on the patient’s body habitus but is typically a couple of minutes on modern TOF scanners, nearly half that of previous-generation scanners. Traditionally, a whole-body PET/CT refers to a scan extending from skull base to midthigh, although studies can include the extremities and brain, depending on the situation.

Although most PET/CT studies are performed without intravenous CT contrast, its use has been increasing because it helps identify normal structures and makes pathology more conspicuous. Water can be used to distend the stomach and duodenum. Dilute oral or water-equivalent negative oral contrast are also acceptable. Attenuation correction can help overcome any questions or artifacts if dense contrast builds up, causing artificially elevated counts.

Displays include a three-dimensional maximum-intensity projection (MIP) image and sagittal, coronal, and axial fused and unfused slices. Software can fuse PET images to CT scans performed at other times or to an MR image if desired. If the examination was performed on a dedicated PET/MR camera, it is still advisable to compare the study to a recent CT in order to visualize some abnormalities, such as small lung nodules.

Pharyngeal and Parapharyngeal

Mild activity is normally present in the salivary glands. Marked uptake is often seen in oropharyngeal lymphoid tissue, including the palatine and lingual tonsils. Asymmetry can occur normally or as the result of therapy and inflammation but may make the evaluation for tumor more difficult. Diffuse marked uptake is often seen in the vocal cords and oropharynx and is increased from speaking. In vocal cord paralysis, unilateral uptake may occur in the normal vocal cord, along with decreased activity in the contralateral abnormal vocal cord ( Fig. 12.6 ).

F-18 fluorodeoxyglucose (FDG) positron emission tomography with computed tomography (PET/CT) images (computed tomography [CT], left; positron emission tomography [PET], center; fused, right ) at the level of the larynx in a patient previously treated for lung cancer reveal marked asymmetrical increased activity in the left vocal cord but no mass—from right vocal cord paralysis and compensatory hypertrophy on the left.

Myocardial Metabolism

Minimizing cardiac activity is desirable when evaluating cancer. The myocardium uses glucose as an optional fuel source. In a fasting state, fatty acid metabolism dominates over glycolysis, leading to decreased FDG uptake. However, fasting yields inconsistent results, and significant cardiac uptake is seen in up to 50% of fasting patients, often very heterogeneous in the left ventricle. Glucose loading, such as done for a cardiac viability study, increases glycolysis and, therefore, FDG uptake. Benign, fairly intense activity is occasionally seen in the intraatrial septal fat.

Urinary Excretion

Activity in excreted urine can create interpretation difficulties. Although the ureters usually appear as long, tubular structures, they can be seen as very focal areas of activity that may be confused with tumor or lymph node metastasis. Correlation with CT and MIP images can help confirm ureter activity or rule out a soft tissue lesion. In addition, activity in the filling bladder can obscure lesions in the pelvis, and urine contamination on the skin may be difficult to differentiate from an actual superficial lesion.

Gastrointestinal Tract

The esophagus normally shows no significant uptake. Nonspecific focal or more diffuse activity could be due to inflammation from reflux. In general, this is less than that seen with cancer or acute radiation. Significant activity in the stomach, especially when collapsed, can limit the usefulness of F-18 FDG in the evaluation of gastric adenocarcinoma or lymphoma. Highly variable activity in both the small and large bowel is especially problematic because it may obscure tumor in the bowel and mesentery. Focal transient activity is frequently seen in the small bowel, possibly the result of lymphoid tissue uptake. Marked uptake in the bowel can occur from metformin. Inflammation, such as from colitis, inflammatory bowel disease, appendicitis, and diverticulitis, can cause radiotracer accumulation ( Fig. 12.7 ). However, these diseases should cause corresponding changes on CT: fat stranding, inflammatory fluid collections, changes in the bowel wall, and air within forming abscesses.

Computed tomography (CT) and fused images from positron emission tomography with computed tomography (PET/CT) performed for lung cancer show stranding in the fat around the sigmoid colon on CT and focal radiotracer uptake in the area of a diverticulum, consistent with diverticulitis.

Reproductive Organs

Cyclical changes can be seen normally in the uterus and ovaries in premenopausal women ( Fig. 12.8 ). Uniform, diffuse, mild to moderate endometrial uptake normally occurs, with maximal uptake occurring during menstruation (menstrual cycle days 0–4) and near ovulation (approximately day 14). Activity is lower during proliferative (days 7–13) and secretory (days 15–28) phases. Normal activity can occur in the ovaries related to ovulation and occasionally in association with follicle growth and the development of the corpus luteum cyst. Increased F-18 FDG uptake can be seen in benign uterine leiomyomas and endometrioma. In men, the testes vary widely but often show high-F-18 FDG levels normally.

Two different young women (with breast cancer and lymphoma in the chest) showing benign activity related to cyclical changes from the menstrual cycle in the uterus (A) and in the right ovary along the periphery of a small adnexal cyst related to ovulation (B). Follow-up studies performed to restage cancer were then performed at a different point in the cycle.

Thyroid Disease

Thyroid activity is normally low or absent; however, multiple uptake patterns can occur ( Fig. 12.9 ). Diffusely increased uptake may be seen in thyroiditis, radiation thyroiditis, and Graves’ disease. The significance of low-level diffuse activity in patients without identifiable thyroid disease is uncertain; it may be normal or the result of subclinical thyroiditis. Focal uptake can be seen in benign adenomatous nodules. However, focal activity can be the result of malignancy in 30% to 50% of cases, and evaluation with ultrasound is warranted to determine whether a biopsy is needed.

Patterns of thyroid activity. The normal thyroid should show no significant fluorodeoxyglucose (FDG) uptake. (A) Diffuse activity can be seen in benign thyroiditis such as Graves’ disease, and multifocal activity (B) can be due to multinodular goiter. (C) Focal activity, however, is associated with a malignant thyroid nodule in 30% to 50% of cases and requires follow-up by ultrasound and then possibly with fine-needle aspiration.

Brown Adipose Tissue Activation

Brown fat (or BAT) plays a role in nonshivering heat generation and can be stimulated by the adrenergic system as well as the cold ( Fig. 12.10 ). It is particularly important in the young but is also occasionally seen in adults. When BAT stimulation is present, F-18 FDG uptake is seen in the fat of the supraclavicular region and neck and occasionally in the upper mediastinum and suprarenal regions. Uptake frequently occurs bilaterally in the region of costovertebral junctions. Sedatives (e.g., lorazepam or diazepam) and beta-adrenergic blockers (e.g., 20 mg oral propranolol) are sometimes used to decrease this uptake, although the effectiveness is variable. Rather, it is generally preferred to keep the patient warm for a period before injection until the examination is complete because this tends to be more effective. In some cases, a scan may have to be repeated because it may be difficult to rule out lymph node involvement such as from lymphoma ( Fig. 12.11 ).

Brown adipose tissue (BAT) or “brown fat,” which helps generate heat (more common in the young), can cause benign activity in the fat of the neck and supraclavicular region, sometimes involving the thoracic inlet and fat around the diaphragm, along with bilateral costovertebral junction uptake, likely related to stimulation of the ganglia at the nerve root. Activity in the right antecubital region is residual from the injection.

In some cases, it may be difficult to exclude tumor involvement in lymph nodes when brown adipose tissue (BAT) activity (left) is present because the pattern may be nodular, as seen in lymphoma (right), or when the activity occurs in areas where lymph nodes seen on computed tomography (CT).

Inflammation, Infection, and Trauma

One of the greatest challenges that arises with F-18 FDG is uptake that occurs in infectious and inflammatory processes, which can be difficult to differentiate from malignancy. In infections, the cause has been attributed to glycolytic activity in leukocytes and the impact of molecules associated with inflammation (e.g., cytokines) on the glut-1 transporters. Infections such as pneumonia will have intense radiotracer accumulation. Inflammatory uptake in a lymph node or mass cannot be reliably differentiated from malignancy. Such findings are commonly problematic in sarcoidosis and granulomatous disease (e.g., histoplasmosis and tuberculosis) in the chest ( Fig. 12.12 and Fig. 12.13 ). Other inflammatory processes in the lungs, such as occupational lung diseases and active interstitial fibrosis and pneumonitis, may also cause markedly abnormal uptake.

Marked uptake (right) is seen in areas of interstitial fibrosis on computed tomography (CT) (left) as a result of occupational lung disease. This level of activity could also be seen from pneumonia or sarcoid.

Pulmonary sarcoid can show marked uptake (right) in prominent or enlarged lymph nodes (left) . Although this can be difficult to differentiate from lymphoma, evidence of granulomatous disease may be seen, such as partially calcified lymph nodes.

Low-level radiotracer can be seen in atherosclerotic plaque and higher levels in arteritis. Mild F-18 FDG may routinely localize to vascular bypass graft walls. However, if more focal intense activity is seen, the CT should be examined for signs of infection or abscess, such as gas, fluid collections, or stranding. Abdominal wall surgical mesh and biliary stents may remain hot indefinitely.

Healing fractures normally accumulate F-18 FDG, but evidence of fracture should be clear on CT ( Fig. 12.14 ). Because PET is more sensitive than CT for bone metastasis, the lack of a fracture on CT could mean the activity is caused by metastatic disease, even if no lytic or blastic CT change is seen. Arthritis can cause increased activity, with activity on both sides of the joint, and increased activity can also be seen around the joint capsule or surrounding soft tissues, with CT fusion helping confirm lack of bone involvement.

F-18 fluorodeoxyglucose (FDG) uptake in fracture. (A) Computed tomography (CT) shows a left rib fracture (arrow) after biopsy of lung cancer. (B) Positron emission tomography (PET) shows uptake in the fracture and the left suprahilar mass, which is not well seen on the single noncontrast CT slice.

Effects of Therapy

Therapy often causes an inflammatory response resulting in increased activity ( Figs. 12.15 and 12.16 ). No definitive rules indicate how long to wait after therapy to perform a PET scan. At times, repeat or even serial imaging is needed to confirm that a change is iatrogenic. Waiting 2 to 4 weeks or so after procedures will help minimize the impact of surgery ( Fig. 12.17 ). Delaying the PET for 2 to 3 months is often recommended after external-beam radiation due to expected acute inflammation and increased uptake. Although this may allow soft tissues to return to background, activity intensifies and often remains high over time in the lungs. However, the pattern of radiation change will mirror the evolution of scarring, with air bronchograms occurring on the CT, and uptake is normally fairly homogeneous if no residual tumor is present ( Fig. 12.18 ). Bones within the radiation port usually show decreased activity after a short interval.

Positive positron emission tomography (PET) scan from talc pleurodesis shows calcified pleura plaques on computed tomography (CT; upper ) associated with marked uptake on PET (lower) that can last indefinitely. Posttherapy changes can be extensive or focal and can be difficult to distinguish from infection or mesothelioma.

Intense pleural activity is seen in mesothelioma (A, B) with early contralateral right hilar (A) and left adrenal metastases (C).

Postoperative change. (A) Two weeks after laparotomy, the computed tomography (CT) scan shows secondary changes in the midline anterior abdominal wall. Stranding of the left-lower-quadrant peritoneal fat around a fluorodeoxyglucose (FDG)-avid tumor implant could be increased by the recent procedure. (B) Activity can be indefinitely increased when associated with mesh, as here in the midline abdominal wall.

Fluorodeoxyglucose (FDG) posttherapy uptake. Computed tomography (CT) and positron emission tomography (PET) images show radiation changes in the posterior medial left lung 3 months after external-beam radiation therapy. The uptake may decrease slightly on follow-up scans, but marked uptake typically persists in the lungs.

F-18 FDG accumulates in the bone marrow as a result of marrow stimulation from anemia, marrow-stimulating drugs (filgrastim [Neupogen] or epoetin alfa [Procrit]), or certain cancer therapies. This activity may be intense enough to obscure underlying lesions, and although usually more homogeneous than changes from tumor ( Fig. 12.19 ), it can be patchy and asymmetrical, particularly in the long bones. Because the duration of these marrow-stimulating agents is frequently long lasting, it may not be practical to delay a study until their effects subside.

Patterns of bone marrow fluorodeoxyglucose (FDG) uptake. (A) Diffuse uptake in the marrow is frequently seen in patients with cancer after therapy with colony-stimulating factors. (B) Osseous metastases usually present with heterogeneous focal lesions.

Chemotherapy often causes a lesion to appear to worsen on PET. The impact can be minimized by delaying a study for at least 2 weeks after treatment, but in some cases, a several-week delay or waiting until just before beginning the next chemotherapy cycle is optimal. There is, however, some evidence suggesting that imaging early after chemotherapy can better predict long-term response in certain tumors, most notably in lymphoma. In some cases, therapy causes a change in the thymus, known as thymic rebound, where the normal low-level shield-shaped uptake in the anterior mediastinum in younger patients intensifies and the organ increases in size on CT ( Fig. 12.20 ). It is important not to confuse this with residual active or worsening lymphoma.

Benign fluorodeoxyglucose (FDG) uptake in the thymus. Area of uptake above the heart (arrow) in the typical configuration of the thymus (A) corresponds to a normal thymus (B) on computed tomography (CT). After chemotherapy, this uptake may be even more intense, the so-called thymic rebound.

Lymphoma

Lymphomas can be divided into Hodgkin’s lymphoma (HL) in approximately 10% of cases and non-Hodgkin’s lymphoma (NHL) in the remainder. Characterization also depends on the type of lymphocyte the tumor arises from: NHL can originate from T cells or B cells, whereas HL involves the B lymphocytes, and numerous subtypes have been identified under these main groupings. Each individual cancer can follow an aggressive, moderate, or more indolent course, but even cases that initially behave in a low-grade manner can undergo malignant transformation, turning highly aggressive and frequently fatal. Patients may also relapse after remission, and in such cases, tumors are often refractory to therapies.

HL progression tends to involve contiguous nodal chains and lymphoproliferative structures. It most frequently presents with painless supraclavicular or cervical adenopathy (60%–80%), axillary adenopathy (30%), and/or mediastinal mass (50%–60%). Disease outside of the lymph nodes is rare (10% to 15%), but when it happens, involvement is most often in the lung, bone marrow, bone, or liver. Disease in NHL does not tend to spread in a similar orderly fashion, and patients frequently present initially with widespread disease.

Survival has improved over the years but is worse if disease is not localized. In HL, the overall 5-year survival rate of greater than 90% decreases to 77% for distant involvement, and for NHL, the overall survival rate of more than 86% falls to roughly 63% when disease is no longer localized. Accurate staging and assessment of treatment response can help prevent unnecessary or ineffective therapy, which, given the high cure rates and long survival times, may be especially important to decrease toxicity from therapy. However, the tumor, node, metastasis (TNM) system commonly used for solid tumors is not as useful for lymphoma.

Methods used for staging and assessment of therapy response have evolved over the years. The Ann Arbor staging system has been widely used for years, relying on lesion location and size changes in lymph nodes, lymphoproliferative tissue, and other organs ( Box 12.4 ). Over the years, classification and grading systems have evolved to better reflect actual changes in tumor activity as opposed to the location of lesions. This is essential because the presence of fibrosis and scar can mean lesions seen on CT do not fully resolve, even after tumor has been successfully eradicated ( Fig. 12.26 ). However, metabolic activity on PET tends to be proportional to tumor grade and can better identify and differentiate sites of active disease from scarring. Changes in F-18 FDG metabolic activity on PET/CT can be used to significantly improve the accuracy concerning changing disease status over anatomical measurement alone on CT or MR. In order to better standardize descriptions of lesion intensity, the Deauville Criteria established a 5-point scale, comparing maximal to background structures:

• 1
  

  = no activity above background

  
  
• 2
  

  ≤ mediastinal blood pool

  
  
• 3
  

  > mediastinum

  
  
• 4
  

  > liver (moderately)

  
  
• 5
  

  >> liver (markedly)

Box 12.4

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