Positron Emission Tomography-Magnetic Resonance Imaging in Oncologic Diseases of the Male and Female Pelvis Andres A. Kohan, MD, Raj Mohan Paspulati, MD, Tracy Sherertz, MD, Hugh Mihaloew, and Karin Herrmann, MD, PhD

Introduction

T

he human pelvis harbors a variety of organs and structures that can be at the origin of developing neoplasms. The clinical and diagnostic workup, the staging, and the appropriate treatment and disease follow-up of these neoplasms are diverse and complex and depend on the organ and tumor type, among other factors. Similarly, the individual diagnostic algorithms and the value of imaging in these algorithms vary between organs and tumor types. The possibility to directly access the target tissue and organ via percutaneous, transrectal, transvaginal, or transurethral approaches offers many options for the diagnosis and staging of the disease and may make one think that imaging is a less requested diagnostic tool. At the same time, a large variety of imaging modalities are nowadays available to assist in the diagnostic workup of oncologic diseases in general and in the diseases of the pelvis in particular. Although constantly improving imaging technology and newly developing imaging techniques are at the disposition of the clinician, oftentimes their diagnostic effect and evidence-based value seem underestimated or remain to be determined. Conversely, for many oncologic diseases of the pelvis, the value of imaging in diagnosing and staging is well established, documented, and accepted knowledge. Ultrasound (US) of the female pelvis, as an example, is a cost-effective and widely and readily available imaging tool, providing comprehensive information in most instances, despite being operator dependent. The endovaginal approach significantly improves its diagnostic performance.1 Computed tomography (CT) is the standard of care to assess the metastatic spread of disease for pelvic malignancies. To complement the diagnostic value of CT with functional

Department of Radiology, University Hospitals Case Medical Center, Cleveland, OH. Address reprint requests to Karin Herrmann, MD, Department of Radiology, University Hospitals Case Medical Center, 11100 Euclid Ave, Cleveland, OH 44106. E-mail: [email protected]

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http://dx.doi.org/10.1053/j.ro.2014.04.002 0037-198X/& 2014 Elsevier Inc. All rights reserved.

information about tumor metabolism, 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) imaging, specifically FDG-PET/CT, is recommended to enforce the staging of pelvic malignancies. PET/CT improves the wholebody assessment. Simultaneously, PET information can be used to estimate tumor aggressiveness, predict and monitor treatment response, and detect residual tumor.2 However, the value of CT or PET/CT for local staging of pelvic malignancies is limited because of the poor soft tissue contrast and sensitivity to artifacts from the surrounding osseous pelvis. A notable weakness of PET/CT, in particular, is its limited spatial resolution and the reduced sensitivity for metastatic lesions of small size (typically o6 mm). Moreover, certain tumors lack the appropriate FDG avidity that is required for diagnostic purposes. Over the past years, magnetic resonance imaging (MRI) has gained significant importance in the local staging of various neoplastic disorders of the pelvis, including rectal cancer, prostate cancer, cervical cancer, and endometrial cancer, among others. However, the expensive nature of MRI creates hesitation to fully explore its capacities as a staging tool despite its superb soft tissue contrast and comprehensive information. The addition of various multiparametric techniques such as diffusion-weighted imaging (DWI), dynamic contrast imaging, and perfusion quantification plus MR spectroscopy has increased its utility and has helped to promote MRI as a tool of guidance for radiation therapy planning and in challenging diagnostic conditions. Moreover, MRI has demonstrated superiority over all other imaging modalities in the detection of liver metastasis.3-5 Particularly, the detection of smaller metastatic lesions is improved with hepatospecific contrast agents in MRI.4-6 The advent of PET/MRI now opens new possibilities to push the boundaries of diagnostic accuracy in these fields in combining the strengths of 2 individual devices in 1. Although none of the available imaging modalities can provide a comprehensive TNM staging of a pelvic malignancy in a single examination, PET/MRI raises the hope to represent this comprehensive diagnostic imaging tool.

Fem - PET/MR in oncologic disease of the pelvis This article reviews the role of diagnostic imaging modalities in the staging of various malignancies of the male and female pelvis, describes the current experience with PET/MRI in these diseases, and briefly discusses the potential value of PET/MRI based on recent literature in this field. Diseases related to the gastrointestinal tract have been addressed in another article of this issue.

Female Pelvis Endometrial Cancer In the United States, the fourth most common gynecologic cancer is uterine cancer. Besides uterine cervical cancer, 2 major categories of malignant neoplasms develop in the uterus: endometrial carcinoma and uterine sarcoma. Uterine cancer typically presents with postmenopausal bleeding. Although the 5-year survival rate has increased to 80%, recurrent cancers and advanced stages are associated with poor prognosis. Primary staging of endometrial cancer is typically performed after surgical treatment, and pretreatment imaging plays a minor role. Endovaginal US is a very effective tool for the local staging of this disease, with sensitivities and specificities ranging between 50% and 89% and 81% and 100%, respectively.7 Although MRI has an exquisite soft tissue contrast and very high accuracy in staging endometrial cancer, the high cost and the limited availability are oftentimes downsides of the modality. Specific techniques such as DWI have proven to even provide prognostic capacity in that low apparent diffusion coefficient (ADC) of endometrial cancer is associated with lower disease-free survival.8 Regarding FDG-PET/CT, there is evidence that it outperforms conventional standard-of-care imaging with CT and MRI alone in the detection of metastatic lymph node (LN) involvement and tumor recurrence.9-11 However, PET/CT has not reached the level of standard-of-care imaging for all cases with uterine cancer with evidence base. According to the National Comprehensive Cancer Network guidelines for uterine cancer, imaging with CT/MRI and MRI or PET is currently accepted if considered clinically indicated but not as the standard of care. MRI may be performed if cervical and extramural involvement is suspected, which would obviate or alter surgical management. In addition, MRI and PET are accepted in the workup “based on symptoms.”12 The role of PET/MRI in this setting is not determined. As a new hybrid modality, there is need for evidence of value. Certainly, there is interest in combining the strength of PET in the detection of recurrence and nodal staging with the strengths of MRI, primarily its soft tissue contrast capabilities. A certain value can also be seen in using PET/MRI for the assessment of treatment response and radiation therapy planning in the case of recurrence. Assessment of treatment response can be challenging for both modalities individually, MRI and PET/CT, which is why the sensitivity and specificity of the combined MRI and PET approach may improve the overall accuracy in this setting. In our preliminary experience, PET/MRI is distinctly helpful in (1) advanced endometrial cancer for staging and treatment

335 planning, (2) a posttreatment setting of recurrence, and (3) equivocal cases where other methods failed to determine the exact origin and extent of the neoplastic disease. In advanced endometrial cancer, PET/MRI can be helpful to clarify the degree and extent of disease beyond clinical staging with the Federation Internationale de Gynécologie et dʼObstétrique (FIGO) classification and PET or PET/CT. The additional information gained from MRI over PET is essentially used for the treatment planning in radiation oncology. Relying on PET or PET/CT as the single imaging modality in the pretreatment scenario carries the risk of overestimating or underestimating disease if the tumor demonstrates a heterogeneous pattern of metabolic activity and heterogeneous morphology. Furthermore, the absolute FDG avidity of these tumors can vary, depending on their histologic type. Particularly, mucinous tumors have the tendency to show less metabolic activity on FDG-PET imaging. Combining the morphologic information from MR images with the pattern of metabolic activity improves the overall understanding of the true clinical situation. The precise visualization of the anatomical relationship between the tumor and the adjacent organs, such as the bladder and the rectum, is pivotal for radiation therapy planning. It helps to protect these critical organs from unnecessary radiation and thus reduce radiation-related side effects. An example of a tumor mismatch between true morphologic tumor extent and PET avidity is illustrated in Figure 1. As a result, PET/MRI is perceived to be superior to PET alone or PET/CT in planning appropriate target zones for radiation therapy in such cases. Another important benefit of combining PET and MRI is the comprehensive TNM staging of the tumors of these patients in a single examination. A comprehensive PET/MRI imaging protocol including high-resolution MRI of the pelvis and whole-body MRI is routinely performed in our institution to assess for both local disease extent and peripheral secondary neoplastic spread. Such a comprehensive protocol can be performed in approximately 1 hour. This allows streamlining the workflow for patients and physicians with only 1 visit for diagnostic imaging, and it is well accepted. Our workflow and imaging protocol is illustrated in Figure 2. To what extent PET/MRI with these benefits outperforms current imaging modalities remains to be determined.

Cervical Cancer Cancer of the cervix is the third most common gynecologic cancer in developed countries and ranks first in countries with restricted access to health care. Overall, 80% of all newly diagnosed cervical cancers occur in underdeveloped countries.13,14 Most cervical cancers (90%) present as the squamous subtype. Cervical cancer is highly associated with human papilloma virus infections. Metastatic spread occurs mainly along the pelvic and retroperitoneal lymphatic drainage pathways. In advanced disease, hematogenous spread to the lungs, liver, and bones can be observed.10 Worldwide, the most widely used staging system for cervical cancer is the FIGO classification. The TNM classification is

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Figure 1 PET/MRI in a patient with local tumor recurrence from endometrial cancer. T2-weighted axial (A) and sagittal (B) MR images, axial (C) and sagittal (D) PET image derived from PET/MRI, axial (E) and sagittal reconstructed T1w postGd WB mDIXON (F) sequence, and fused axial and sagittal PET/MR images (G and H) of an 83-year-old woman with endometrial cancer recurrence. MR images demonstrates local recurrence of endometrial cancer in an 83-year-old woman. The heterogeneous morphology of the tumor consisting of a cystic peripheral component (A, small arrows) and a solid, more central portion (A, asterisk) can be noted. Along the left-sided tumor boundaries (A, large arrow), there is vascular invasion into the small veins within the parametrium. Including this area into the target area for radiation is essential. Furthermore, the mixed tumor abuts and displaces the rectum posteriorly. A second solid tumor nodule is seen at the vaginal cuff, indenting on the posterior bladder wall (B, arrow). Both are in critical locations for radiation therapy planning. On PET scans, the FDG avidity is confined to the solid tumor components in this mixed solid-cystic malignancy (C and D, red cross). It can be noted that the cystic components demonstrate a void of tracer activity. This entails the risk of underestimation of the true tumor size because of the cystic component. Gd, gadolinium; T1w, T1-weighted. (Color version of figure is available online.)

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Figure 2 Workflow for combined PET/MRI of whole-body MRI and dedicated pelvic MRI. This graph illustrates the imaging protocol and workflow for any combined PET/MRI with pelvic malignancy and is applied for the workup of gynecologic cancers and rectal cancer. (Color version of figure is available online.)

essentially based on the same criteria. The FIGO staging is based entirely on clinical assessment, relying on physical examination, colposcopy, cystoscopy, sigmoidoscopy, and radiography, sometimes including intravenous urography.15 Exact initial staging is critical in these patients, as it determines the appropriate treatment, which is either surgery alone or surgery combined with chemoradiation therapy. Again, the first step of primary staging is the physical examination, sometimes with advanced investigation under anesthesia. Despite the high performance of imaging and the noninvasiveness of potential imaging techniques such as MRI, the physical examination is still considered standard of care for staging.16 However, PET/CT or MRI scans or both are routinely ordered to aid in radiation therapy planning for cervical cancer. MRIʼs accuracy in staging disease is as high as 90%. Its negative predictive value is 95% for parametrial invasion.10 The strength of PET/CT is the assessment of nodal and hematogenous metastatic spread as a prognostic factor.10 Tumor eventually recurs in one-third of the treated patients.17 Generally, differentiation between cancer recurrence and fibrotic tissue can be challenging with any imaging. Both PET/CT and MRI have been proven beneficiary in this clinical context and can help predict recurrence and treatment response.18 MRI has a number of tools to offer to address this issue using multiparametric imaging, such as DWI and, lately, dynamic contrast-enhanced imaging, in addition to morphologic imaging only.19,20 For example, ADC values have been found useful in determining recurrence or metastasis vs normal tissue with a reported sensitivity and specificity of 100% and 87.5%, respectively.19 Furthermore, pretreatment ADC values between complete responders (lower ADC) and partial responders (higher ADC) are significantly different and can be used as guidance.20 PET/CT is an excellent method for LN and distant metastatic assessment, and both examinations can help predict treatment response and recurrence with high accuracy. For example, progression-free survival is higher in patients with negative

findings on PET/CT images after treatment than in those with positive findings.18 Currently, investigators have looked into the value of combined PET with MRI in gynecologic cancers in performing retrospective digital fusion of the imaging data of both modalities.21-23 A study was able to demonstrate that PET fused with MRI outperformed PET/CT in the assessment of gynecologic malignancies23 in general. Overall, 80% of the analyzed study population in this study presented with cervical cancer, which demonstrates that these results support the special significance in this particular group. Another study looking at the digital fusion of PET and MR images was able to confirm these results and demonstrated a higher diagnostic performance of this combined fusion imaging approach over PET/ CT21 in detecting LN metastasis. This allows the assumption that nodal staging may be a specific focus for the use of PET/MRI in the future. Whether PET/MRI as the new hybrid modality will significantly outperform the accuracy of each of its individual imaging components remains to be determined. However, the initial experience with PET/MRI in an oncologic setting shows another potential significant benefit of PET/MRI: the support for radiotherapy planning of cervical cancers. The recent introduction of intensity-modulated radiotherapy (IMRT) based on 3-dimensional (3D) treatment planning has refined radiotherapy techniques for cervical cancer and pelvic cancers in general. With IMRT, the tumor and LNs are delineated on CT images and the radiotherapy doses are delivered in a more conformal method to the affected tissues only. This allows a greater dose delivery to the target sites and at the same time reduces the radiation to unaffected pelvic structures, thus limiting toxicity. Traditionally, radiotherapy planning has involved measurements of the gross tumor volume on CT images. However, in IMRT, the highly conformal dose distribution increases the need for imaging modalities that allow for improved tumor definition beyond what CT can offer.

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Figure 3 PET/MRI in brachytherapy treatment planning. For radiation therapy planning, 3D high-resolution T2w MR sequence, PET/MR, and CT images are uploaded in a software module. The tumor is delineated and contoured based on the information from all imaging modalities. After positioning of the brachytherapy applicator and treatment, the follow-up for treatment response control is performed with MRI and applicator in place. T2w, T2-weighted. (Color version of figure is available online.)

Meanwhile, MRI has developed into an accepted tool to support radiotherapy planning. Literature has demonstrated a high accuracy of MRI to determine tumor volume and thereby makes it also most suitable to define target volumes so that dose outside the target is limited, leading to a reduction in radiation injury to the small and the large bowels and the bladder.24 Although so far relying on tumor volume only has shown discrepancies between MRI and CT, the outcomes of this technique are under investigation. In our institution, not only CT and structural MRI are included into the (3D) treatment planning for radiotherapy of cervical cancers. Multiparametric MRI information and PET results from PET/MRI are fused with the CT data set for radiation therapy planning to include as much functional information about the tumor tissue as possible (Fig. 3). The combination of high-resolution morphologic and functional information facilitates a more precise disease contouring for tumor dose prescription. The availability of MRIcompatible applicators and brachytherapy devices supports this multimodality approach even further. Of particular help for radiation therapy planning of cervical cancers is the fact that MRI can demonstrate the extent of parametrial invasion with high accuracy. Specifically, the ability to delineate tumor infiltration into the bladder wall or the rectal wall is of dedicated value. This not only changes the local staging from T3-T4, but both the rectum and the urinary bladder are critical organs for radiation oncologists to spare from high-dose radiation. Moreover, in PET, exact tumor delineation and contouring of FDG-avid tumors close to the bladder can be challenging because of the tracer accumulation in the bladder. Both scatter and poor spatial resolution of PET make the distinction of the 2 structures sometimes difficult. The morphologic information from MR images then becomes essential (Fig. 4). Particularly in cervical cancer, where the tumor is in such close vicinity to the bladder, it is of tremendous benefit that PET and MR images are acquired at almost the same time. Hereby, the change in bladder volume is less of a problem and the alignment of the anatomical structures in both imaging

modalities is facilitated. This is a benefit of PET/MRI over retrospective digital image fusion. PET/MRI also seems promising in the nodal staging of cervical cancer. In our experience, adding the information of FDG activity, such as size, shape, signal intensity, and diffusion restriction, to the indicators of metastatic involvement in MRI helps to increase the diagnostic confidence. This comprehensive approach to cervical cancer radiotherapy planning based on CT and PET/MRI takes into account almost any possible imaging information about tumor location, tumor extent, and active tumor tissue to guarantee exact tumor delineation and appropriate dose distribution. Further studies have to prove the evidence of improved therapy and outcome with this approach.

Ovarian Cancer Ovarian cancer is the most lethal gynecologic malignancy. Because of its silent nature, timely diagnosis and appropriate treatment are often delayed. At the time of diagnosis, up to two-thirds of patients present with disseminated disease.25 The survival rate is as low as 25% in these cases, as opposed to 90% in patients with localized disease.26 The most challenging aspects of this disease are appropriate and early detection and assessment of disease dissemination. US is widely used to evaluate adnexal lesions as it is noninvasive or minimally invasive, cheap, and can provide a first approximation to the etiology of the lesion. If a lesion is detected using US and is deemed inconclusive, typically, further evaluation follows with the goal to discriminate between benign adnexal lesions and indeterminate or frankly malignant adnexal lesions that would need surgical attention. Gadolinium-enhanced MRI has yielded the highest posttest probability in comparison with CT, Doppler US, and MRI without gadolinium, with reported sensitivity and specificity of 100% and 94%, respectively.27 Given the unfortunate situation that many patients are diagnosed in the advanced stage of disease, oftentimes, the first imaging modality to detect adnexal malignancy is CT. The patientʼs symptoms and complaints may be nonspecific and

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Figure 4 PET/MRI in a patient with cervical cancer and primary tumor staging. T2w turbo spin-echo (TSE) MRI sequence in axial (A and B) and sagittal (C) planes of a patient with cervical cancer. A high-resolution MR image clearly demonstrates the invasion of the posterior bladder wall (B and C, black arrow) and the parametrial invasion (B and C, white arrows). There is a preserved fat plane between the tumor and the rectum. It can be noted that an abnormally enlarged lymph node at the left pelvic wall with heterogeneous signal on T2w images is suggestive of metastatic involvement (A, white arrow). PET derived from PET/MRI (D), T2w TSE sequence in axial and sagittal orientation (E), and PET/MR–fused images of the same patient with cervical cancer. In PET scans, the exact margin of the FDG-avid tumor and the posterior bladder wall is difficult to determine (red cross). MRI helps to more accurately distinguish the planes. Quasi-simultaneous image acquisition allows for good alignment between PET and MR images: a benefit of PET/MRI over digital image fusion techniques. It can be noted that the focal tracer uptake identified in the sagittal image (D, black arrow) is actually related to the bowel and not a lymph node. T2w, T2-weighted. (Color version of figure is available online.)

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Figure 5 PET/MRI in a patient with ovarian cancer recurrence presenting as a nodular serosal implant. T2w MRI sequence (A) and PET/MRI (B) in a patient with ovarian cancer recurrence. A small focal nodular peritoneal implant is identified on PET/MRI. It can be noted that with MRI only, the detection of the small nodular serosal implant is very difficult (red cross). There is the risk that PET would misinterpret the focally increased tracer uptake close to a bowel loop as physiological. However, in combination, the diagnostic confidence is significantly improved for this lesion to be a malignant implant. T2w, T2-weighted. (Color version of figure is available online.)

even mimicking gastrointestinal disease, which prompts the study. Epithelial ovarian tumors most frequently present as cystic lesions with solid components; however, an overlap between malignant, indeterminate, and benign lesions is considerable. In this context, PET/CT has been proven to be useful to differentiate between benign and borderline or malignant tumors, with reported sensitivity and specificity of 62%-100% and 85%-100%, respectively,26 and to assess for peritoneal spread. PET/CT is currently regarded as the most accurate noninvasive technique for detection of peritoneal spread.28 The introduction of DWI has fostered MRI as an equally powerful diagnostic tool with encouraging results.28,29 Whole-body DWI demonstrated 94% accuracy for primary tumor characterization and higher accuracy for peritoneal staging (91%) than PET/CT (71%) and contrast-enhanced CT (75%) when compared with surgery.30 For ovarian cancer surveillance, the National Comprehensive Cancer Network recommends serial visits, including pelvic examinations, and measurement of CA 125 levels, if they are initially elevated. Imaging is recommended if clinically indicated, preferably with PET scans.31 The clinical examination is still preferred over imaging as most patients with recurrence present with clinical symptoms. Conventional CT is claimed to have limited sensitivity and specificity of 40%-93% and 50%-98%, respectively.31 Although MRI has been shown to be superior to CT in the detection of lesions, especially on the peritoneal surface of bowel, in the cul-de-sac, in the vaginal vault, and in the bladder, it has still not gained preference, given the limited availability and high costs; thus, CT remains the modality of choice to detect disease relapse.31 As recurrent ovarian cancer benefits from cytoreductive therapy, preoperative assessment is important. PET/CT outperforms CT and MRI in the detection of recurrent disease, as a meta-analysis has shown that the

sensitivity and specificity are 91% and 88 % for PET/CT, 79% and 84% for CT, and 75% and 78% for MRI, respectively.32 However, more modern techniques, such as DWI, have not been included in this meta-analysis, which overall might underestimate the capability of MRI to detect ovarian cancer recurrence, as mentioned earlier.30 Given this background, it is reasonable to predict that PET/ MRI is prone to play an important role in ovarian cancer for all stages of disease, particularly when combining multiparametric MRI with PET. From our experience, the beneficial synergy of the 2 modalities can already be seen in several scenarios: (1) the use of DWI in MRI is helpful to detect small peritoneal seeds that escape detection on PET scans alone because of limited spatial resolution, (2) better anatomical reference with MR images facilitates the distinction of FDG-avid peritoneal serosal bowel implants from FDG hypermetabolism due to bowel motility, and (3) MRI can improve the detection and exact lesion localization in critical interfaces, such as the subdiaphragmatic area, where PET has misregistration because of respiratory motion (Fig. 2). As for most cancers currently under investigation, the superior performance and significant incremental value of PET/MRI over current imaging standards remains to be proven for it to gain attention as a preferable diagnostic tool in ovarian cancer staging. In our experience, the combined information of morphology from high-resolution MR images, including DW images, and metabolic activity from PET scans increases the diagnostic confidence about the presence of malignant disease. The dominant role of PET/MRI in ovarian cancer in our institution is to support the surgical decision whether cytoreductive therapy is an option and if there is disease in locations that are difficult to access even during laparotomy, such as the perihepatic subdiaphragmatic space. Especially in small lesions of ovarian cancer recurrence, the combination of 2 powerful techniques has been shown to

Fem - PET/MR in oncologic disease of the pelvis enhance the diagnostic outcome. Furthermore, peritoneal implants close to the bowel are challenging for both modalities individually. In PET, the distinction from physiological bowel activity may be difficult; in MRI, soft tissue nodules may appear in clusters of bowel loops and may not be easily detected. The combination of the 2 techniques considerably improves the diagnostic confidence in these cases. An example of this is demonstrated in Figure 5.

Male Pelvis Prostate Cancer Prostate cancer is the most common malignancy in men and ranks third in cancer-related deaths.33 Of 6 male individuals, 1 will develop prostate cancer during their lifetime.34 The widespread use of prostate-specific antigen screening and digital examination has substantially decreased the number of advanced prostate cancer cases at the time of diagnosis.33 The most important prognostic factors are the Gleason score and the clinical stage at the time of initial diagnosis. Imaging is important for diagnosis in equivocal cases after biopsy and to guide treatment decisions and treatment planning. Transrectal US is widely used to determine gland volume, guide systematic tissue sampling, and place brachytherapy seeds. However, its incremental value over digital rectal examination for initial diagnosis is questionable if not coupled with systematic sampling. MRI, including morphologic and multiparametric imaging, has emerged as the most comprehensive and effective imaging tool for the local staging of prostate cancer if findings on both TRUS and systematic sampling are unremarkable34 and yet suspicion for malignancy is high. Various studies have demonstrated that multiparametric MRI is more accurate than any other imaging modality in determining the T category of the disease and more specifically to distinguish T2 from T3 categories.34 Furthermore, multiparametric imaging with DWI has a significant potential to predict tumor aggressiveness, as lower ADC values correlate with higher Gleason scores.35 In addition, dynamic contrast-enhanced imaging is decisively valuable to detect and localize recurrence after radiotherapy with a reported sensitivity and specificity of 90% and 81%, respectively.36 Moreover, MR spectroscopy is a decisive tool in cases where morphologic imaging with T2-weighted sequences has limitations, such as in the transitional zone cancers where low background signal intensity reduces appropriate delineation of malignant tissue.33 MRI has gained importance for prostate cancer imaging, having recently been published an evidence-based expert consensus for clinical indications and structured reporting Prostate imaging-reporting and data system (PI-RADS) as a reflection of the increase usage of this imaging tool in this setting.37 CT has its role in the LN staging and assessment of metastatic spread in patients with a prostate-specific antigen level 420, Gleason score 47, or a category superior or equal to III.33 The sensitivity and specificity of CT vary significantly in the literature, depending on the selected subpopulation of patients with prostate cancer.33 For detection of bone

341 metastasis, Tc99m bone scintigraphy is currently recommended because of its capacity to detect bone marrow involvement even before osteoblastic reaction becomes visible in the bone scan.36 CT is inferior to Tc99m bone scintigraphy and MRI.33,36 Recent literature claims whole-body MRI to outperform bone scintigraphy for this indication.36 There is general agreement that PET/CT with 18F-FDG has no role in diagnosing or staging prostate cancer.38 By contrast, studies with PET/CT using 11C-choline, 18Fcholine, or 11C-acetate have shown encouraging results regarding LN and bone metastasis detection,36,38,39 with reported sensitivity and positive predictive value for 11Ccholine in the preoperative setting of 85%-100% and 80%90%, respectively.36,38 The ideal imaging modality to embrace all needs for diagnostic and therapeutic management of this disease is to detect and locate the disease at an early stage, accurately stage it locally and distally, guide biopsy when needed, assess treatment response, and accurately determine relapse during follow-up. In a context where no particular imaging method has an edge over the other in any of the mentioned areas, combination of what appears to be the strongest imaging tool in local staging with the new radiotracers being studied for PET/CT that are showing encouraging results could as well become the closest imaging method to the ideal described before. Furthermore, Park et al40 reported that retrospective fusion of PET, performed with 11C-choline, with MR images acquired in a separate machine had a better performance than either study alone. As to the previously described requirement of being able to direct biopsy, there is at least 1 case report in a patient with high suspicion of cancer and negative findings on biopsy that shows how the use of 11C-choline and MR multiparametric imaging in a truly hybrid PET/MRI allowed guidance for a successful biopsy.41

Testicular Cancer Testicular cancer is the most common malignancy in men aged between 15 and 35 years and is usually discovered incidentally as an asymptomatic lump in one of the testicles. Testicular neoplasms are classified as germ cell tumors and non–germ cell tumors. Non–germ cell tumors are less frequent and usually benign. Germ cell tumors are further subdivided into the following 2 entities: seminoma and nonseminoma. Seminomas account for 50% of the germ cell tumors. They are highly radiosensitive and have an overall cure rate of more than 90%.42 Tumors with seminomatous and nonseminomatous tissue are more aggressive and have poor prognosis; they require more aggressive treatment. Nonseminoma tumors metastasize early to the LNs and the lung. Serum markers such as alpha fetoprotein, in nonseminomas, or β-human chorionic gonadotropin, in either type of tumor, can be used to help in the diagnosis or follow-up of germ cell tumors. However, only 45% of patients with relapse may have detectable serum markers at the time of their diagnosis.43 Imaging plays a significant role in the management

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342 of these tumor entities, given the fact that transscrotal biopsy is associated with an increased risk of tumor spread. Scrotal US is an excellent method to locally assess the testicles. It benefits from the proximity to skin and the use of high-frequency transducers. In patients with incidental findings of microcalcifications in the testicles, periodical US examinations for tumor screening are recommended as these individuals are at an increased risk of developing cancer. However, in the presence of a suspicious mass, US remains limited for LN and distant metastatic spread evaluation, and the false-negative rates is as high as 70%.42 Computed tomography is the mainstay for nodal staging and follow-up of treated patients even though it also has a high rate of false negatives ranging between 30% and 59% and a false-positive rate of 25%.42 As for the role of MRI, few studies that focus on the ability to distinguish between seminoma and nonseminoma tumors44 rather than staging capabilities are available. Conversely, PET/CT is highly efficacious in detecting metastatic spread in this patient population, with reported sensitivity, specificity, positive predictive value, and negative predictive value of 93.3%, 97%, 93.3%, and 97%, respectively.45 PET is reportedly superior to all other conventional imaging methods in predicting the presence of viable residual tumor, even when combined with either MRI or CT.45 Finally, PET helps to predict treatment response to high-dose salvage chemotherapy early on in patients who presented with relapse.45,46 As there is little knowledge on the benefit of MRI in staging or following up of this disease, little can be predicted on the effect or role of PET/MRI and its potential incremental value over PET/CT. The aspect of reducing radiation exposure in patients who would undergo PET/MRI instead of PET/CT in sparing the CT component is a valuable argument in favor of PET/MRI as the target population is young. However, the clinical potential of PET/MRI needs to be further evaluated in studies.

Bladder Cancer The ninth most common cancer related to death in men is bladder cancer. It typically presents with macrohematuria. The most common histopathologic subtype is transitional cell carcinoma (490%), and much less frequent are squamous cell (5%) and adenocarcinoma (2%) subtypes.47 Overall, 70% of bladder cancers are superficial and poorly detected with noninvasive imaging techniques such as radiography, CT, or even MRI. They are successfully managed with diagnostic and therapeutic endoscopic procedures such as cystoscopy. Only 30% of all bladder cancers develop into high-risk malignancies with tendency to metastasize and risk of death.47 If these tumors are addressed with CT, the sensitivity and specificity are limited to 85% and 94%, respectively.48 This is mainly because of the limited soft tissue resolution of CT, which does not allow distinguishing the muscular layers of the bladder. Regardless of this fact, CT and CT urography are the most often performed imaging studies in the presence of a hematuria.

US is another widespread modality and is often used in the first-pass evaluation of hematuria. However, it is limited for the assessment of muscular layers and lymphadenopathy. Contrast-enhanced US, when performed, can improve an accuracy of 2D US from 72.1%-88.4%. In lesions o5 mm, the accuracy decreases significantly.48 MRI has a reported accuracy of 85% in differentiating muscular layers and depth of infiltration. It is 82% accurate in organ-confined disease.48 When including the potential of DWI, MRI is capable of predicting response to chemoradiation therapy in muscle-invasive tumors with a sensitivity, specificity, and accuracy of 92%, 90%, and 91%, respectively. DWI is also helpful in the determination of nodal involvement with high sensitivity and specificity of 76.4% and 89.4%, respectively.49 The role of PET/CT again lies in staging distant and nodal metastatic disease. Assessment of local disease is hampered because of the excretion and accumulation of FDG metabolites in the urine. Catheterization with or without bladder irrigation, voiding, and use of diuretics have been proposed to mitigate this effect; however, this did not entail the establishment of this modality for local staging. Accurate assessment of both LN and distant metastatic spread seems challenging with imaging. A recent meta-analysis on PET/ CT found a pooled sensitivity and specificity of 82% and 89%, respectively, for staging and restaging metastatic disease in bladder cancer.50 In view of these limitations, it may be allowed to question that PET/MRI has a lot to offer to improve the situation. No substantial literature is available to support any value of PET/ MRI in bladder cancer currently.

Summary PET/MRI has the potential to provide comprehensive TNM staging in the primary diagnosis for most malignancies in the pelvis. Furthermore, significant value is to be seen in the assessment of recurrence, where both modalities individually but even more jointly in 1 examination have considerable strengths. For radiation therapy, planning PET/MRI is of significant value as it provides high-resolution morphologic information from MR images and the functional metabolic information from PET scans. As PET is already integrated in the guidelines of the care of gynecologic malignancies, MRI is a significant add-on to facilitate and improve the local treatment planning. However, for all applications, the incremental clinical, diagnostic, and prognostic value of PET/MRI over current imaging standards remains to be proven.

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