Urologic applications of positron emission tomography (PET) have centered primarily in oncology using
18F-2- deoxy-
D-glucose (FDG), although a variety of tracers and specialized applications have been approached in limited studies. The primary clinical application of diagnostic imaging in urology relates to the management of the chief urologic malignancies including renal cancer, bladder cancer, prostate cancer, and testicular cancer. Testicular cancer is covered in a separate chapter of this volume (Chapter 14). Upper urinary tract obstruction, relative size and function of kidneys, presence of infection, and urinary tract congenital abnormalities are still assessed by anatomic imaging, contrast fluoroscopy, ultrasound, mag- netic resonance imaging (MRI), computed tomography (CT), and existing radionuclide studies (1). Renal blood flow (2, 3) and blood flow and metabolism (4) as well as renal angiotensin receptor distribution (5) have been quantitatively measured using PET techniques; however, practical clinical applications of these studies have not yet emerged.
The applications in urologic malignancies parallels other oncologic applications in the body, that is, static imaging using FDG or other tracers preferentially accu- mulated by the malignant tissue for purposes of diagnosis and staging. The relevance of FDG-PET in the clinical management of urologic malignancies is, as with any ma- lignancy, inextricably related to the need for diagnostic imaging in the management of the disease. Hence, experi- ence with FDG PET in urologic malignancies must be viewed in the context of the contemporary management of these diseases.
Renal Malignancy
Renal malignancies include renal cell carcinoma (RCC), transitional cell carcinoma, squamous cell carcinoma, lymphoma, and metastatic neoplasm, usually lung cancer or melanoma. Renal cell carcinoma, the most common
malignant neoplasm of the kidney, is primarily a surgi- cally managed disease. Surgical extirpation is the only ef- fective means of curing RCC. In patients with advanced disease, medical treatment options currently offer little in terms of improved survival or palliation. Hence, most renal masses that are not unequivocally benign on anatomic imaging are removed in attempt to provide a surgical cure, providing that there is no diagnostic imaging evidence the neoplasm has spread beyond the local compartment of Gerota’s fascia. The prognosis for patients with RCC is most strongly influenced by stage at the time of surgery (6), although the histology and nuclear grade of the primary neoplasm influence long-term sur- vival (7, 8) among RCC of the same grade.
The role of diagnostic imaging in the management of renal malignancy, then, is twofold: (1) characterization of the renal mass, that is, determining whether it is a malig- nant neoplasm requiring extirpation, and (2) staging, that is, determining the presence of locoregional and distant metastases.
Historically, diagnostic imaging evaluation of a renal mass was performed as part of evaluation of hematuria, flank pain, or a palpable mass. Increasingly, as a result of the widespread use of cross-sectional imaging modalities such as CT and ultrasound, detection of a renal mass is serendipitous (9), and consequently RCC is discovered at a much earlier stage. In the absence of clear-cut evidence of metastases on CT or ultrasound, the principal task of diagnostic imaging of a renal mass is distinguishing cysts (always benign) from complex cysts (sometimes malig- nant) from solid masses (usually malignant). Simple cysts are well characterized on contrast CT and ultrasound.
More-complex cystic renal masses are placed in categories first described by Bosniak (10). Bosniak category I, the simple cysts, require no further evaluation. Category II complex cysts can be managed by directed anatomic imaging follow-up. The category III and IV cystic masses, however, typically require surgical exploration or extirpa- tion, respectively, as there is currently no reliable method of excluding a malignancy (11). Hence, PET potentially
24316
PET and PET/CT Imaging in Urologic Tumors
Paul D. Shreve
anatomic imaging (13). Preoperative needle biopsy of solid renal masses is generally eschewed because of inher- ent sampling errors and the possibility of spread of neo- plastic cells along the needle tract (14). Hence, solid renal masses without evidence of metastatic disease are gener- ally resected; there is little role for additional imaging characterization of a solid renal mass greater than 3 cm in diameter. Characterization of the small renal mass, however, is taking on greater importance for reasons of the growing incidental detection of solid masses less than 3 cm in diameter and the conservative management of such masses, particularly in settings where minimally in- vasive surgery and nephron-sparing surgery are contem- plated (15–17). PET potentially could aid noninvasive characterization of the malignant potential of small renal masses.
Elevated FDG uptake in renal malignancy was de- scribed in RCC by Wahl et al. (18) in an animal tumor model and a limited number of human subjects more than a decade ago. Characterization of a solid renal mass has been described in initial limited series (19, 20) in which surgically proven RCC renal masses were identified as positive on FDG-PET. However, the renal masses in these series were large, in many cases readily identifiable in the PET images by sheer bulk even if the tumor was iso- intense with the nonmalignant adjacent renal parenchyma. False-negatives tended to be small renal
histologic classification or Fuhrman nuclear grade and SUV was evident. In a retrospective chart review by Kang et al., (24) among 66 patients with known or suspected RCC the sensitivity of FDG-PET for the primary tumor was 60% compared to 92% for contrast-enhanced CT. In a series of 35 patients, Aide et al. (25) reported a sensitivity of 47% and specificity of 80% for FDG-PET characteriza- tion of renal masses. Hence, there may be inherent limita- tions in using the tracer FDG for evaluation of RCC in general, and renal masses in particular, because of the relatively modest FDG avidity of a significant fraction of malignant renal tumors.
Renal cell carcinoma can be quite FDG-avid, and when FDG-avid is readily evident as a renal mass or metastatic deposit (Figure 16.1). Non- or relatively low FDG-avid RCC can be entirely occult on FDG-PET, however, even when obvious on anatomic imaging (Figure 16.2). In the detection of locoregional and distant metastases, FDG- PET sensitivity and specificity were 63% to 77% and 75%
to 100%, respectively (24–27). Positive predictive value appears to high, in excess of 90% (28), whereas generally the negative predictive value is too low to be clinically useful (for example, a negative study does not exclude malignancy). At least in one series (26), true-positive FDG-PET metastases were anatomically abnormal by size criteria (greater than 1.7 cm), whereas the false-negative metastases ranged in size from 0.7 to 1.4 cm, consistent
a b c
Figure 16.1. FDG avid renal cell carcinoma. Contrast-enhanced (CT) (a), FDG-PET with attenuation cor- rection (b), and fusion image (c) demonstrate a large left renal cell carcinoma with central necrosis.
FDG-PET demonstrates glucose me- tabolism along the peripheral rim of tumor and in left paraaortic and aortocaval lymph nodes (arrows).
with a relatively modest, on average, FDG tracer uptake by RCC metastases. Regarding osseous metastases, whereas FDG-PET can detect lytic metastases occult on conventional bone scan (29), in a retrospective chart review of 66 patients, sensitivity and specificity of FDG- PET were 77% and 100%, respectively, in comparison to 94% and 87%, respectively, for combined CT and bone scan (24). Hence, FDG-PET alone is probably not suited for detection of recurrent or metastatic RCC. Given the high positive predictive value of a positive FDG-PET finding, however, combined FDG-PET/CT may well have advantages over CT alone in the staging of RCC and the detection of recurrence.
Given the limitations of FDG as a tracer for renal malig- nancies, primarily the modest and variable FDG uptake and urinary excretory route, other tracers have been investi- gated, including amino acids and amino acid analogues (30). Acetate is also retained by RCC but rapidly cleared from the renal parenchyma as CO
2, and with no urinary ex- cretion (4). Higher average SUV and tumor to renal cortex values are obtained within 10 min of tracer injection com- pared to FDG at 1 h post injection, and the highest acetate tracer accumulation was found in granulocytic tumors (31).
Although such tracers of amino acid transport or lipid- related metabolism may have a role in characterizing a small renal mass or response to therapy, detecting RCC in complex renal masses and metastatic disease requires high consistent tracer uptake in the renal neoplasm, and such has not yet been demonstrated with this tracer.
Bladder Cancer
Bladder and related urothelial malignancies account for approximately 4% of clinical malignancies. Of the three
major urothelial malignancies, transitional cell carci- noma, squamous cell carcinoma, and adenocarcinoma, transitional cell carcinoma is by far the most common in both the bladder and upper urinary tract. In contempo- rary clinical practice, bladder cancer is diagnosed primar- ily by cystoscopy and upper urinary tract urothelial malignancy by CT urography or retrograde contrast ureteropylography. The most important prognostic factor in bladder cancer is the development of, and degree of, bladder wall invasion (32). Diagnostic imaging is most helpful in assessing the depth of muscle invasion and degree of perivesical involvement. Such distinctions require, in addition to high contrast between neoplasm and nonneoplastic tissue, high spatial resolution. PET would be expected to have limited utility in determining bladder wall invasion and adjacent spread. It is possible to visualize primary bladder cancer on FDG-PET when ap- propriate maneuvers are taken to minimize urinary FDG tracer activity (Figure 16.3).
Locoregional nodal staging is critical for proper man- agement of bladder cancer patients. As with N staging elsewhere, the size criteria of nodal involvement used with anatomic imaging is of limited accuracy (33).
Hence, PET with FDG or other tumor-specific tracers could provide increased accuracy in N stage of bladder cancer, as has been demonstrated with several other ma- lignancies. Distant metastatic disease, most commonly osseous, pulmonary, and hepatic metastases, is impor- tant in patients with invasive bladder cancer. It is possi- ble PET could offer some improvement in detection of osseous or hepatic metastases analogous to that ob- served in other malignancies such as lung or esophageal cancer.
Metastases not closely associated with the upper urinary tract and bladder are readily detected due to relatively good apparent FDG avidity of transitional cell
a b
Figure 16.2. Non-FDG-avid lymph node metastasis of renal cell carcinoma.
Contrast-enhanced CT (a) depicts en- larged left paraaortic lymph node that is not FDG avid on the FDG-PET image with attenuation correction (b) (arrows).
carcinoma of the bladder (Figure 16.3). Limited pilot studies (34, 35) have demonstrated that metastatic bladder cancer is FDG-avid and that involved local lymph nodes as small as 9 mm could be detected, whereas smaller involved nodes (less than 5 mm) were false nega- tive. In a series of 64 patients, Bachor et al. (36) reported a sensitivity of 67% and a specificity of 86% for FDG-PET detection of pelvic lymph node metastases of bladder cancer. Osseous metastases of bladder cancer are readily detected on FDG-PET, but the relative accuracy of FDG- PET versus conventional bone scintigraphy has yet to be fully addressed. Bladder cancer appears to have relatively consistent avidity for FDG, and adding FDG-PET to con- ventional anatomic evaluation of locoregional and distant spread of bladder cancer such as with PET/CT may well prove clinically valuable.
As elsewhere in the urinary tract, alternative tracers that do not undergo urinary excretion, or can be imaged before the arrival of the excreted urinary tracer activity, have been investigated in an attempt to obviate the con- founding effects of urinary tract excretion.
11C-L methion- ine was used in a limited series to investigate the PET detection of primary bladder cancer (37). T4, most T3, and 2 of 4 of T2 primary bladder cancers were detected.
The T staging was not superior to anatomic imaging, and there were insufficient proven cases of nodal metastases to evaluate accuracy of local lymph node metastases. In a preliminary series, de Jong et al. (38) reported detection of 10 of 18 primary bladder cancers with
11C-choline PET. In 2 patients, pelvic lymph node metastases were visualized;
however, again there were insufficient proven cases of
nodal metastases in the series to evaluate the accuracy for local lymph node metastases.
In addition to locoregional lymph node staging, differ- entiating postradiation therapy scar from recurrent tumor in patients treated for locally advanced disease and assess- ment of neoadjuvant therapy response are areas warranting further investigation of PET with FDG and other tracers.
Prostate Cancer
The role of diagnostic imaging in the management of prostate cancer is both as rapidly evolving and as contro- versial as the clinical management of the disease.
Although two decades ago staging before prostatectomy with bone scintigraphy was common, today the manage- ment of prostate cancer is varied, with far less reliance on surgery and the routine use of serum markers (prostate- specific antigen) to assess disease progression and re- sponse to therapy. Because the prostate itself is easily accessed via the rectal vault, very high resolution anatomic imaging by ultrasound or MRI is possible (39).
Biopsy of all sectors of the prostate gland, either randomly or assisted by ultrasound guidance, is routine and hence tumor histologic grade is readily obtained at initial diag- nosis. The potential roles for diagnostic imaging of prostate cancer include diagnosis of primary disease, de- termination of extracapsular spread, and detection of lo- coregional lymph node metastases and distant metastatic spread. In addition, emerging roles include guidance of
c d
Figure 16.3. FDG-avid left bladder wall thickening (a and b, arrows) correspond- ing to a primary urothelial neoplasm. A solitary hepatic metastasis is also in- tensely FDG-avid (c and d, arrows). The bilateral FDG uptake in the groins is physiologic in aortofemoral bypass graft (a and b, arrowheads).
local therapy in patients with organ-confined disease and assessment of tumor response to systemic therapy in pa- tients with advanced metastatic disease.
As with other neoplasms, the value of PET in clinical management is dependent on the avidity of prostate cancer for a given tracer such as FDG and the utility of competing modalities or procedures. Early observations with prostate cancer found relatively low avidity in un- treated metastatic disease of sufficient bulk to be readily detected by PET. SUV generally were less than 4, and al- though soft tissue disease that was anatomically abnor- mal was detected, the sensitivity of FDG-PET relative to bone scintigraphy was poor (40, 41). Although the reason for the low relative uptake is not fully understood, the rel- atively slow growth of most prostate cancer may relate to low glucose metabolism. It is of interest, however, that advanced prostate cancer refractory to systemic therapy demonstrates consistently moderately high FDG uptake (42). In such patients, the metastatic lesions in both bone and soft tissue are well demonstrated on FDG-PET (Figure 16.4).
The relatively low avidity of untreated prostate cancer for FDG and the confounding effect of adjacent bladder urinary tracer activity would suggest FDG-PET is not likely to be useful in diagnosis of organ-confined disease.
In a series of 24 patients with organ-confined prostate cancer in which urinary tracer activity in the bladder was minimized, only 1 (4% sensitivity) was detected (43).
Tumor volume ranged from 1.2 to 10.4 mL with a mean of 6.9 mL. The failure of detection most likely reflects the low tumor to background achieved with FDG. Similar disap- pointing results were reported for the detection of local recurrence of prostate cancer in patients treated by prostatectomy (44), also attributed to the relatively low avidity of prostate cancer for FDG.
Capsular penetration is a key milestone in stage of prostate cancer, separating traditionally surgically re- sectable (stage A and B of the Jewett–Whitmore classification) from nonresectable disease (stage C) and a poor prognostic indicator associated with metastatic disease. The distinction between involvement of the capsule of the prostate gland from penetration of the capsule requires exceeding high resolution; it is not a task for which scintigraphic imaging is well suited. Both tran- srectal ultrasound and endorectal coil MR offer the level of imaging spatial resolution to potentially address this important distinction, with best results reported to date with endorectal coil MR (45). Applications of PET to assess capsular penetration have not been reported.
In addition to capsular penetration, staging of locore- gional lymph nodes remains an important task for imaging in patients considered for prostatectomy who are at high risk for nodal spread based on Gleason score and serum prostate-specific antigen (PSA). The limitations of anatomic imaging in the diagnosis of lymph node metastatic involvement of obturator, iliac, and retroperi- toneal lymph nodes in the setting of prostate cancer are well established (46, 47). Again, likely reflecting the rela- tively low FDG avidity of prostate cancer, preliminary as- sessment of FDG-PET detection of pelvic lymph node metastases on FDG-PET was disappointing (48). In one series, detection of abdominal or pelvic lymph node metastases was no better than anatomic assessment (49).
Reported sensitivity for pelvic lymph node metastases in a series of 24 patients with rising serum prostate-specific antigen was, however, 75% with a specificity of 100% (50).
It does appear that detection of both locoregional and distant metastatic prostate cancer by FDG-PET is most feasible in patients with untreated, or in particular, pro- gressive, disease (42, 51).
Distant metastatic disease includes bone, abdominal and thoracic lymph nodes, and liver. Detection of lymph node and liver metastases has been reported (40), but no substantial series assessing the accuracy of FDG-PET in the detection of distant soft tissue metastases has been published. Compared to bone scan, FDG-PET appeared to be substantially inferior in the detection of osseous metas- tases, with sensitivity relative to bone scan ranging from
Figure 16.4. FDG-PET of advanced metastatic prostate cancer. Whole-body anterior projection attenuation-corrected FDG-PET image of a patient with advanced metastatic prostate cancer, refractory to hormone therapy. Substantial FDG uptake is present in the right iliac wing (arrow) and left iliac lymph nodes (arrowheads).
were subsequently found to have disease progression by clinical criteria (53).
The generally low FDG avidity of prostate cancer and the confounding effect of the urinary excretory route of FDG has fostered interest in other positron tracers.
Exogenous choline is used by cells in the synthesis of phosphatidylcholine, the most abundant phospholipid in cell membranes.
11C-Choline was first investigated as a tumor-imaging tracer in primary brain tumors (54) and subsequently in several cancers including prostate cancer (55, 56). Both soft tissue and bone metastases were identified, with SUVs ranging from 2.5 to 9, with a mean in the 4.5 to 5.0 range, whereas normal prostate was in the 2 to 3 range. Blood pool clears within minutes, and tracer is generally retained in the tumor with little change.
Pancreas, liver, and renal parenchyma had high uptake and retention, with little urinary tract activity. The absence of urinary tracer activity in the early dynamic phase of imaging allows for some utility in the detection of locally recurrent prostate cancer in the setting of rising serum prostate-specific antigen, although detection of the foci of primary cancer within the prostate gland is limited by tracer uptake in benign prostatic hypertrophy (57–59).
11
C-Choline PET was 80% sensitive and 96% specific in the staging of pelvic lymph node metastases in a prospective series of 67 patients (60).
18
F-Labeled choline derivatives have subsequently been synthesized and tested, including
18F-fluoromethyl choline (61) and
18F-fluoroethylcholine (62).
Fluromethylcholine most closely matches the in vivo phosphorylation rate of choline and appears to be the pre- ferred
18F-labeled choline analogue for PET imaging (63).
Both soft tissue and bone metastases are readily identified with fluorocholine, with SUVs ranging from 2.5 to as high as 10, but on average roughly 4.5 in untreated prostate cancer (Figure 16.5). In addition to high liver, pancreas, and bowel activity, fluorocholine undergoes urinary ex- cretion. The rapid tumor uptake and blood pool clear- ance, however, does permit early imaging of the prostate and adjacent tissues before arrival of urinary tracer in the bladder. In comparison to FDG-PET,
18F-fluorocholine PET was generally better in detection of primary lesions and osseous and soft tissue metastases on initial clinical evaluation (64). Detection of foci of primary cancer within the prostate gland was, similar to
11C-choline, limited by
tracer uptake in benign prostatic hypertrophy and prosta- titis (65, 66).
Altered anabolic metabolism in cancers can be detected on PET using
11C-acetate. First used to assess oxidative metabolism in myocardium, radioacetate has been shown to accumulate in tissues with high levels of anabolic me- tabolism such as the pancreas (67) and certain cancers in- cluding renal cell carcinoma (4, 31), nasopharyngeal and ovarian cancer (68), and prostate cancer (69). With
11C- acetate PET, blood pool tracer activity clears within 2 min and tumor visualization nears maximum within about 5 min after tracer injection, with very slow clearance of re- tained tracer thereafter. Pancreas is the only abdominal organ with consistently high uptake, with variable mod- erate uptake in liver and portions of bowel. Renal parenchymal activity clears within 10 min (following oxi- dation to carbon dioxide), and there is no appreciable urinary excretion. Untreated prostate cancer is readily de- tected in both soft tissue and bone metastases (Figure 16.6), with SUVs ranging from 2.5 to more than 10 but av- eraging about 4.5 (70, 71). The absence of urinary excre- tion permits unencumbered visualization of the prostate
Figure 16.5. Fluorocholine PET of recurrent prostate cancer. Whole-body attenuation- corrected coronal image located posterior to the bladder acquired 10–40 min post [18F]fluoromethylcholine administration. Focal uptake in the prostate bed is suggestive of recurrent disease in patient with serum PSA of 15.7 mg/dL and rising.
and adjacent structures. Normal prostate tissue is, however, associated with tracer uptake with SUVs ranging from 1.1 to 4.5 with a mean of 2.8 (72), limiting potential assessment of primary prostate cancer. In a limited series of 15 patients comparing
11C-acetate PET with FDG-PET, locoregional metastases were visualized slightly better on
11
C-acetate PET, whereas distant metastatic lesions were slightly more conspicuous on FDG-PET (73). A limited series of 12 patients found the degree of
11C-acetate and
11
C-choline tracer uptake in prostate cancer or its metas- tases to be nearly identical (74).
As with acetate and choline PET tracers, amino acid tracers have been investigated both as a probe of an alter- nate metabolic pathway and as a strategy to avoid the con- founding effects of urinary tracer in the bladder. In patients with progressive metastatic prostate cancer,
11C-
L
-methionine uptake in metastatic lesions was consis- tently higher than FDG uptake and demonstrated progressing metastatic lesions more consistently than did FDG on PET imaging (75, 76). Some success was also re- ported in using
11C-
L-methionine PET to direct biopsy in patients with rising serum prostate-specific antigen and negative routine biopsies (77).
Although there has been considerable enthusiasm for
11
C-choline,
18F-fluorocholine,
11C-acetate, and
11C-
L-me- thionine as solutions to the limitations of FDG in PET imaging of prostate cancer, it should be noted that the average uptake of these tracers in prostate cancer, al- though higher than FDG, is still modest on average, with SUV less than 5.0. Such uptake is about one-half of the average values observed with FDG in the cancers, such as lung cancer, where PET has shown superior accuracy over anatomic imaging. Thus, although selected cases with high uptake of these tracers (SUV 8 or higher) suggest high potential diagnostic accuracy, the experience with moderate or average uptake in FDG-PET, such as with breast cancer, indicates the applications of these tracers to prostate cancer may be more limited. One potential ap- plication where detection of small deposits of tumor is not critical is assessment of tumor response to therapy in pa- tients with advanced prostate cancer. Serum prostate- specific antigen is widely used for determining response to therapy of prostate cancer but is not always reliable, particularly in advanced hormone-refractory prostate cancer (78). There is some evidence of prognostic value of FDG (glucose metabolism) and
11C-methionine (amino
Figure 16.6. Acetate PET of primary and metastatic prostate cancer. Transaxial images of pelvis above and at the base of the bladder 10 min after 11C-acetate administration (upper images) demonstrate osseous metastasis (arrows) in the sacrum, posterior acetabulum, and pubic ramus, as well as primary prostate cancer/prostate tissue (arrowheads). Note absence of urinary tracer activity in the bladder. Comparison images at the same transaxial levels 1 h after FDG administration (lower images) demonstrate very low FDG uptake (arrows) in the prostate cancer metastases.
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