- Email: [email protected]
MR imaging of pelvic malignancies
Accepted Manuscript Title: PET/MR imaging of pelvic malignancies Author: Axel Wetter M.D. Johannes Gruneisen ¨ M.D. Lale Umutlu M.D. PII: DOI: Reference:
S0720-048X(17)30071-2 http://dx.doi.org/doi:10.1016/j.ejrad.2017.02.026 EURR 7746
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
8-12-2016 13-2-2017 15-2-2017
Please cite this article as: Wetter A, Grddotuneisen J, Umutlu L, PET/MR imaging of pelvic malignancies, European Journal of Radiology (2017), http://dx.doi.org/10.1016/j.ejrad.2017.02.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PET/MR imaging of pelvic malignancies Axel Wetter, M.D.1* Johannes Grüneisen, M.D.1
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Lale Umutlu, M.D.1
Department of Diagnostic and Interventional Radiology and Neuroradiology,
Corresponding Author:
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University Hospital Essen, Hufelandstraße 55, 45122 Essen
Axel Wetter, M.D.
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University Hospital Essen
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Department of Diagnostic and Interventional Radiology and Neuroradiology
Hufelandstraße 55
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45122 Essen
Tel.: 0049-(0)201-723-84522 Fax: 0049-(0)201-723-1563 Email: [email protected]
Review article
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Highlights Integrated PET/MRI with simultaneous acquisition of PET and MRI is an emerging and promising technique in oncologic imaging Imaging of female and male pelvic oncologic diseases like cervical cancer and
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prostate cancer requires a high soft tissue contrast and make these entities especially suitable for PET/MR imaging
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This review article highlights recent publications of PET/MR imaging in both
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entities
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PET/MR imaging of pelvic malignancies
Abstract Integrated PET/MRI is a new technology which allows simultaneous acquisition of
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positron emission tomography and magnetic resonance imaging data during one examination. The technique appears to be particularly appropriate for oncologic
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imaging of female and male pelvic malignancies, as these entities demand a high soft
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tissue contrast and might be further assessed metabolically with PET. The review
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article highlights recent developments of integrated PET/MRI in pelvic malignancies.
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Introduction Since the first publication of images from a commercial clinical Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) scanner in the year 2008 (1), numerous studies have been performed and published in order to analyze and
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evaluate this new technology in clinical routine (2). A clear advantage of integrated PET/MRI is the inherent possibility to combine the high soft tissue contrast of the MR
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component with the metabolic information of the PET component, derived from the
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utilization of different and specific tracers. Therefore, considerable effort has gone into the evaluation of pelvic malignancies with PET/MRI, as these tumor entities
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require a high soft tissue contrast and might be further distinguished with functional MR imaging methods like diffusion weighted imaging (DWI) and dynamic contrast
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enhanced (DCE) imaging techniques. This review article will focus on the latest developments regarding PET/MRI in female and male pelvic malignancies, notably
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cervical carcinoma and prostate cancer.
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PET/MRI in prostate cancer
Imaging of prostate cancer particularly seems to be appropriate for integrated PET/MRI, as the entity can reasonably be examined only with MRI, where the
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anatomical peculiarities of the prostate gland can properly be assessed in contrast to computed tomography. Furthermore, multi-parametric MR imaging of prostate cancer has become the modality of choice, as the combination of morphological (T2weighted imaging) together with functional imaging (DWI and DCE) examines the tumor as complete as possible and weights the parts of multi-parametric imaging differently. This imaging strategy is expressed by the Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2), which was published in 2015 from the American College of Radiology (3). A substantial component of multi-parametric
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prostate MR imaging is represented by diffusion-weighted imaging, being determined as the dominant sequence for tumor detection of the peripheral zone (3). At present, proton-MR spectroscopy plays only a minor role in prostate MR imaging and has been omitted from the latest PI-RADS classification. Recommended MR sequences
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for prostate cancer imaging are high resolution T2-weighted fast spin echo sequences in axial, coronal and sagittal planes, a diffusions-weighted sequence
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including high b-values and a dynamic contrast enhanced imaging sequence (e.g. a
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T1-weighted VIBE sequence obtained every 7 seconds for 5 to 10 minutes). PET imaging of prostate cancer mainly relies on the utilization of radio-labelled
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choline tracers and 68Ga prostate-specific-membrane-antigen (PSMA), both of them representing different approaches of metabolic imaging in prostate cancer. Both
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radio-labelled choline and PSMA tracers are frequently used in PET/MRI of the
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prostate, as well as for the evaluation of primary prostate cancer and recurrent disease. The rationale of examining primary prostate cancer with integrated PET/MRI
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is to optimize tumor detection by using combined morphologic, functional and metabolic information during one examination. This is possible with the most commercial PET/MRI scanners, as the MR scan and the PET scan are operated
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simultaneously. Up to now, certain studies have been performed, mainly yielding at comparison of the information of combined PET/MRI with that of PET or MRI alone. PET/MRI of prostate cancer with radiolabelled choline PET imaging of prostate cancer with radio-labelled choline mainly utilizes carbon-11 choline or 18F-labelled choline analogs, notably 18F-fluoroethylcholine and 18F fluorocholine (4, 5, 6). Looking at 18F choline as the utilized tracer, a most recently published study using 18F fluorocholine came to the conclusion that the combined information of integrated 18F choline PET/MRI has significantly better sensitivity, Page 5 of 24
specificity, positive and negative predicitive values as well as diagnostic performance than multi-parametric MRI alone (7). In this study, 31 patients were examined with a dedicated PET/MRI scanner before radical prostatectomy and histopathology results served as the gold standard. The authors explained the improvement of diagnostic
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accuracy by use of integrated PET/MRI partly with the complementary information of PET and ADC, especially in low Gleason tumors and concluded that integrated 18F
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choline PET/MRI might be a reasonable imaging modality for initial staging with local
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and whole body PET/MR imaging in the future, after confirmation of its additional value for the detection of local spread and distant metastases. Another most recently
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published study provided an interim analysis of an ongoing prospective clinical trial (8) evaluating the value of fusion 18F fluorocholine PET/MRI for detection of
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significant prostate cancer with image-guided prostate biopsy. On the contrary to the study mentioned before, this study was based on fused images from PET/CT and
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multi-parametric MRI with the inherent disadvantage of the required registration of PET and MR images and thus did not represent a “real” simultaneous or integrated
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PET/MRI. However, the authors found that addition of the PET signal (quantified as SUV mean target-to-background ratio) significantly improved detection of Gleason
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>/= 3+4 prostate carcinomas.
A study from de Perrot et al. published in 2014 (9) investigated the additional value of 18
F fluorocholine PET parameters in addition to multi-parametric MRI for tumor
detection. The results of 23 patients who were undergoing radical prostatectomy after hybrid PET/MRI examination indicated a significantly better tumor detection of PET/MRI than multi-parametric MRI alone in the peripheral zone, whereas there was no advantage of PET/MRI in detection of transitional zone tumors. Logistic regression analysis identified SUVmax and ADC as the strongest parameters in PET/MRI, and
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with absent correlation of these parameters, the authors deduced that SUVmax and ADC might be independent biomarkes. A single center prospective clinical trial investigating fused 18F fluorethylcholine (FEC) PET and endorectal MRI in patients with biopsy proven prostate cancer
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scheduled for radical prostatectomy reported a high sensitivity in detection of the
dominant prostate cancer lesion and also stated a significantly better performance of
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fused PET/MRI than endorectal MRI alone (10). However, the MR protocol mainly
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based on T2 weighted images and did not include a real multi-parametric setting including DWI and DCE, therefore the inferior performance of MR imaging in this
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study should be interpreted with caution. Nevertheless, the high quality of the study design with a clear prospective setting and the excellent gold standard with
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reconstructed whole mount sections of the prostate after radical prostatectomy is a
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strong proponent of combining 18F choline PET and MRI in primary prostate cancer. The quoted studies demonstrate the ability of 18F choline PET/MRI to improve
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detection of tumor foci in primary prostate cancer in contrast to MRI alone. This is in contrast to 11C or 18F choline PET/CT studies, where imaging of primary prostate cancer generally is not recommended and is considered to be inferior as compared to
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MRI (11). The inferior soft tissue contrast of PET/CT and the possibility of consideration of both choline metabolism and high resolution MR imaging might explain the different performance of PET/CT and PET/MRI in primary prostate cancer. Suspected recurrent disease after radical prostatectomy is a major problem in prostate cancer management and needs appropriate clarification. If a rising PSA level occurs after definite treatment of prostate cancer, radio-labelled choline PET/CT has been shown to provide valuable information of the site of recurrent disease and has Page 7 of 24
been judged to improve care in patients with biochemical failure (12). Regarding real integrated PET/MRI for detection of recurrent prostate or lymph n ode disease, the literature is scarce up to now. However, a study that investigated fused 18F choline PET/MRI reported of a significantly higher sensitivity, accuracy and negative
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predictive value than multi-parametric MRI or contrast enhanced CT alone on a lesion based analysis. Patient based analysis, however, did not yield significant
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differences between 18F choline PET/MRI and mpMRI alone. The study population
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was small (21 patients), therefore prospective studies with a larger patient collective are needed to provide substantial information of a potential advantage of integrated
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PET/MRI in detecting recurrent disease in biochemical recurrent prostate cancer. An example of a 18F fluorocholine PET positive primary prostate carcinoma and a 18F
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fluorocholine PET positive bone metastasis is shown in figure 1.
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PET/MRI of prostate cancer with 68Ga PSMA
Prostate-specific-membrane-antigen (PSMA) is a membrane bound protein in
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prostate cancer cells, but is at a lower level also expressed for example in the brain or salivary glands. For PET imaging, particular kind of PSMA ligands are used, of whom the most commonly used is 68Ga PSMA-HEBD-CC (full name Glu-NH-CO-NH-
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Lys-(Ahx)-68Ga-(HBED-CC)) (13). The first study of integrated PET/MRI utilizing this tracer was published in 2014 and demonstrated feasibility (14). From 20 patients with biochemical recurrence after definitive treatment of prostate cancer examined, all MRI examinations from integrated PET/MRI were of diagnostic quality. Moreover, PET/MRI could clarify four ambiguous PET/CT findings in three patients. However, this study also reported of an extinction of the PET signal in the scatter corrected PET images of integrated PET/MRI around the kidneys and urinary bladder, the socalled “halo”, in a significant proportion of patients. This “halo” led to significant
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underestimation of SUVs in altogether 7 lesions in 3 patients and was explained by the authors with the unstable scatter correction of integrated PET/MRI systems. In order to prevent false negative results, all PET images from integrated 68Ga PSMAHEBD-CC PET/MRI should be visualized and inspected without scatter correction
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(14). Further recommendations are sufficient hydration, voiding immediately before examination and forced diuresis induced by intravenously administered furosemide to
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minimize the halo artifact. Recently, Eiber et al. evaluated the diagnostic performance
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of 68Ga PSMA-HEBD-CC integrated PET/MRI in comparison to multi-parametric MRI and PET alone (15). The study included 66 consecutive patients, of whom 53 were
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finally eligible for retrospective evaluation. Gold standard was histological sextant based examination of the prostate gland. The study demonstrated that PET/MRI as
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well as PET was superior over multi-parametric MRI on a patient-based analysis as well as on a sextant based analysis. Diagnostic accuracies for prostate cancer
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detection, provided as areas under the curve from a ROC analysis were significantly higher for PET and PET/MRI than for mpMRI alone. No significant differences of the
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AUC were found between PET and PET/MRI. For prostate cancer localization, PET/MRI reached the highest AUC, followed by PET and mpMRI, respectively. The authors concluded that simultaneous 68Ga PSMA-HEBD-CC PET/MRI increased
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diagnostic accuracy in prostate cancer detection and localization and recommended realization of prospective studies to further evaluate PET/MRI in prostate cancer. Among possible study limitations, the authors addressed that only b-values until 800 s/ mm2 were employed, indicating that the employed DWI sequence might be diagnostically less conclusive as if higher b-values would have been used. Examples of 68Ga PSMA PET positive primary prostate carcinomas, local recurrences and lymph nodes are shown in figures 2 – 6.
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To summarize the results of the actual studies regarding PET/MRI in prostate cancer, the method implies a high potential to further improve prostate cancer detection and localization in patients with primary prostate cancer when compared to multiparametric MRI. This might be especially valuable for patients with clinical suspected
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prostate cancer who are scheduled for a second biopsy after the first was negative. Regarding suspected lymph node or bone metastases, which is a major issue in
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methods of CT, PET/CT and bone scintigraphy is necessary.
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prostate cancer patient care, further evaluation and comparison with the standard
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PET/MRI in cervical cancer Despite well-established screening and prevention methods, cancer of the uterine cervix is considered both the third most common cancer type as well as cause of
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cancer-related death in women worldwide (16). Once diagnosed, the prognosis
mainly depends on the stage of the cancer at initial diagnosis. While survival rates of
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microscopic forms of cervical cancer may be as high as 100%, survival rates of stage
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3 and/ or higher are shown to decrease to less than 40% (17). With curative options such as surgery and concurrent chemo-radiotherapy being limited to small local
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tumors (4cm; stages IA, IB1, IIA1), correct high-quality assessment of local tumor extent as well as of lymphonodular and distant metastatic spread is imperative for
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optimized patient management and therapy planning (18). While the reference
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standard for staging still involves clinical examination under anesthesia combined with cystoscopy, proctoscopy, sigmoidoscopy and biopsy (19), current guidelines
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such as the revised FIGO (Federation of Gynaecology and Obstetrics) staging system seize the importance of high-quality imaging diagnostics in recommending the application of cross-sectional imaging for correct tumor staging, particularly
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stressing the superiority of MRI for assessment of local tumor extent (20-22). Based on its inherently high soft-tissue-contrast as well as high spatial resolution imaging capacity, MR imaging has been shown to provide accurate information on important prognostic as well as therapy-crucial factors, such as tumor size, parametrial and pelvic sidewall invasion (23,24), hence it is recommended as an adjunct to clinical assessment. While MRI has been shown superior for evaluation of the local tumor extent (over other cross-sectional imaging modalities), molecular imaging, by means of 18F-FDG-PET/CT, has been demonstrated to enable superior (lymph node) staging, overall restaging and treatment monitoring of gynaecological malignancies Page 11 of 24
(25). Numerous studies underlined the added value of the assessment of metabolic features of lymph nodes, facilitating higher sensitivity and specificity rates for lymph node staging, particularly in patients with locally advanced cervical cancer when comparing PET/CT to MRI (21,26). Pooled sensitivity and specificity rates of PET/CT
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were shown to be as high as 82 and 95% over 56 and 91% in MRI (27). Therefore, PET/CT is considered an accurate imaging alternative to surgical lymph node
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dissection in advanced tumor stages, as micro-metastases may be missed due to
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deficient increase of tracer uptake (26-28). Although FIGO staging does not cover lymphadenopathy, it has been shown that exclusion / detection of lymph node
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metastases displays an important factor for patient prognosis as well as treatment planning (29). Considering the strength of MRI for local staging and the strength of
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PET/CT for lymph node and whole-body staging, the combined analysis of morphologic and metabolic parameters may help to leverage staging of gynaecologic
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malignancies (Figure 7). Until recently, investigators tried to overcome the lack of integrated PET/MR systems, by performing subsequent PET/CT and MR scanning
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and retrospective data fusion. While this is a commonly applied approach for rigid application fields, such as brain imaging, the assessment of structures of the female pelvis demands simultaneous data acquisition, as physiologic peristaltis of the bowel
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system as well as diverging bladder filling may significantly impair correct coregistration of subsequently acquired metabolic and morphologic data. Hence, the recent introduction of integrated PET/MRI scanner systems may help to diminish these problems of correct merging of metabolic and morphologic information and enable a valuable conjunction of the best of both imaging modalities. Although limited, initial studies have reported promising results on the application of integrated PET/MRI for primary staging and restaging of patients with gynaecological malignancies of the female pelvis (30, 31). Grueneisen et al were one of the first to
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report on the feasibility and diagnostic value of integrated PET/MRI for staging of primary cervical cancer. The study comprises a rather small patient cohort of 27 patients with histologically proven cervical cancer and reveals its high diagnostic competence for primary staging in facilitating correct determination of the T-stage in
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85% of the patients as well as sensitivity, specificity and diagnostic accuracy rates for the detection of nodal positive patients of 91%, 94% and 93%, respectively. Apart
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from the promising results for T and N-staging, which should be considered
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preliminary due to the small patient cohort, the study revealed further encouraging information regarding correlations between PET and MRI derived functional
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parameters for grading and tumor size (32). The added value of the metabolic component of PET/MRI was also taken up in another study by Brandmeier et al (33).
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Comparable to a study by Grueneisen et al,. Brandmeier et al investigated the correlation between PET and DWI parameters, showing that the mean SUVmax and
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ADC min of primary tumors and metastases showed a significant inverse correlation, whereas the correlation in recurrent lesions lacked to merit significance, which is
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probably caused by the altered biology of tumor recurrences (32, 34). These results underline the diagnostic potential of simultaneous multi-parametric PET/MRI for the assessment of non-invasice functional biomarkers, demonstrating the strong
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correlation between tumor metabolism and increased cellularity in (primary) cervical cancer lesions (Figure 8). Apart from primary local cancer staging initial investigations have also revealed the diagnostic potential of integrated PET/MRI for radiation planning as well as therapy monitoring. Up to current status, PET/CT has been well-established to define the gross tumor volume for radiation therapy (34, 35). Nevertheless, based on the improved delineation of the local tumor extent in MRI, PET/MRI may bear the potential to replace PET/CT and enable a more precise delineation of the tumor extent combined with the metabolic information and facilitate
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improved target therapy (35). In more advanced tumor stages chemotherapy is commonly applied to reduce the tumor volume. However, while MRI allows for an excellent assessment of the primary tumor, post-therapeutical changes after chemoand/ or radiotherapy may impair the correct differentiation between residual tumor
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and post-therapeutical changes. This may be another important diagnostic application field, which may benefit from the combined analysis of metabolic and
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morphologic tumor features (Figure 9). Apart from its applications for local tumor
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assessment, therapy monitoring and radiation treatment planning, integrated PET/MRI bears the potential for another important application field, by means of
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whole-body staging and restaging. Within the last few years, numerous studies have demonstrated its high diagnostic potential for numerous tumor entities (37-39). This
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may also apply for staging patients with primary and recurrent cervical cancer (30, 31). Various studies investigated the diagnostic competence of integrated PET/MRI
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compared to MRI alone as well as compared to PET/CT. The overall conclusion is that integrated PET/MRI facilitates superior whole-body staging when compared to
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MRI alone and comparable results to PET/CT, while enabling a significant reduction of the applied ionizing radiation (30,31). After initial studies demonstrated its diagnostic competence, yet requiring long examination times, more recent studies put
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the focus on protocol optimization to facilitate shorter overall examination times, while preserving the high diagnostic competence (40, 41). In summary, it is well deserved to conclude that the past 5 years of successful introduction of integrated PET/MRI into research and clinical imaging have demonstrated its high diagnostic potential for simultaneous investigations of the morphologic and metabolic features of malignancies of the female and male pelvis, comprising local and whole-body staging, exclusion of tumor relapse as well as therapy monitoring. Page 14 of 24
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40. Grueneisen J, Schaarschmidt BM, Heubner M et al. Implementation of FASTPET/MRI for whole-body staging of female patients with recurrent pelvic malignancies: A comparison to PET/CT. Eur J Radiol 2015; 84:2097-2102 41. Grueneisen J, Schaarschmidt BM, Beiderwellen K et al. Diagnostic value of diffusion-weighted imaging in simultaneous 18F-FDG PET/MR imaging for
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Figure legends Figure 1 69 year old patient with a histological proven prostate carcinoma who exhibits a
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choline-positive prostate carcinoma of the left transitional and peripheral zone and choline-positive bone metastases.
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A) T2 weighted image in axial orientation shows a large hypo-intense mass of the
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left transitional and peripheral zone and delineation of a hypo-intense area in the right pubic bone (arrows).
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B) Fused 18F Fluorocholine PET/MRI demonstrates intense tracer uptake of the
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prostate carcinoma and also of the metastasis in the right pubic bone.
Figure 2
Ga PSMA PET/MR images from a 59 year old patient after radical prostatectomy.
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examination.
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PSA level was slowly rising after operation to a level of 0.55 ng/ ml at the time of
A) T1-weighted fat-saturated image with contrast in axial orientation depicts a small lymph node just beside the left external iliac artery (arrow). From the
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contrast enhanced images, it was equivocal whether the lymph node was benign or malignant, as it was small with a distinct fatty proportion.
B) However, fused PET/MR image demonstrated pronounced tracer uptake of the lymph node, making it highly suspicious to be a lymph node metastasis.
Figure 3 Multi-parametric 68Ga PSMA-PET/MRI assessment of a biopsy proven primary prostate carcinoma of the left transitional and peripheral zone in a 81 year old
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patient. Patient was referred for initial staging of the recently diagnosed cancer. Distant metastases could not be confirmed with PET/CT and PET/MRI. A) T2-weighted fast spin echo sequence with 3 mm slice thickness depicts a large hypo-intense tumor of the left peripheral zone.
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B) Dynamic-contrast-enhanced imaging of the tumor shows early enhancement of the tumor.
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C) ADC map from Diffusion-weighted imaging with hypo-intense delineation of
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the tumor.
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D) Fused T2 68Ga PSMA PET images with strong tracer uptake of the tumor.
Figure 4
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59 year old patient with slowly rising PSA level up to 7.1 ng/ml and suspected prostate carcinoma. T2 weighted MR imaging demonstrates pronounced hyperplastic
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remodeling of the prostate gland without a clear tumor-suspicious finding. However, a doubtful T2 hypo-intense lesion was found in the left peripheral zone of the prostate.
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DWI did not contribute to further clarification due to a large susceptibility artifact. Ultrasound guided saturation biopsy localized prostate cancer only in the left dorsal area as indicated by PET/MRI.
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A) T2 weighted high resolution T2 weighted image at mid-gland level demonstrates pronounced changes typical for benign prostatic hyperplasia.
B) T2-weighted high resolution image between mid gland and apex depicts a faint hypo-intense small lesion in the left transitional zone. C) Fused 68Ga-PSMA-PET/MR image demonstrates pronounced tracer uptake of the lesion. Saturation biopsy confirmed prostate cancer at this level of the prostate gland.
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Figure 5 Multi-parametric 68Ga PSMA PET/MR Images from a 67 year old patient with a rising PSA level after radical prostatectomy. Patient was referred to the PET/CT and PET/MRI unit for further clarification. PSA level reached 1.1 ng/ml. In the further
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course the Patient was scheduled for radiation therapy of the prostate bed. A) T2 weighted image in axial orientation demonstrates a hypo-intense mass left
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laterally from the vesico-urethral anastomosis.
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B) Dynamic contrast enhanced MR imaging shows this lesion early enhancing. C) Diffusion-weighted image with high b-value (1000s/mm2) depicts the lesion
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hyper-intense, indicating a diffusion restriction of the lesion.
D) Fused PET/MRI image with a strong tracer uptake of the lesion, which was
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diagnosed as recurrent disease in the prostate bed.
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Figure 6
65 year old patient with a rising PSA level after radical prostatectomy. At 68Ga-
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PSMA-PET/MRI examination, PSA reached 0.86 ng/ml. PET/MRI revealed a small lymph node just medially from the pectineus muscle. After PET/MRI, lymphadenectomy was performed and confirmed a single lymph node metastasis.
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A) T1-weighted fat-saturated image after administration of a paramagnetic contrast agent depicts a small lymph node just medially the pectineus muscle, which was overlooked in the morphological images.
B) Fused 68Ga PET/MR image demonstrates strong tracer uptake in the lymph node, which was later histologically confirmed by lymphadenectomy.
Figure 7
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Images of a 47 years-old-patient diagnosed with primary cervical cancer (squamous cell carcinoma). Post-contrast T1w VIBE (A) and T2 TSE images (B) show the manifestation of the tumor confined to the uterine cervix (Tumor stage IB2) which reveals restricted diffusion (D,E) as well as pathologic glucose metabolism after
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image fusion in PET/MRI (C,F).
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Figure 8
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Mutiparametric imaging of a patient with primary cervical cancer. Integrated PET/MRI facilitates the simultaneous assessment of morphological (T2 TSE, image A9,
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metabolic (B), perfusion (C) as well as diffusion features of the tumor.
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Figure 9
Images of a 33 years-old female patient with primary cervical cancer. Prior to the
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initiation of neoadjuvant chemotherapy. MR images (A, T2 TSE; B, T1 VIBE p.c) show a tumor manifestation at the uterine cervix infiltrating the vaginal rim as well as
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the uterus which reveals pathologic glucose metabolism after image fusion in PET/MRI (C, PET/MRI). After completion of initial treatment no focally increased tracer uptake is detectable, indicating complete resection (F, PET/MRI). However, on
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MR images (D, T2 TSE; E, T1 VIBE p.c) there is still suspicion of a tumor residue. After surgical resection, no tumor tissue could be verified histopathologically, confirming the diagnosis based on PET/MRI.
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S0720-048X(17)30071-2 http://dx.doi.org/doi:10.1016/j.ejrad.2017.02.026 EURR 7746
To appear in:
European Journal of Radiology
Received date: Revised date: Accepted date:
8-12-2016 13-2-2017 15-2-2017
Please cite this article as: Wetter A, Grddotuneisen J, Umutlu L, PET/MR imaging of pelvic malignancies, European Journal of Radiology (2017), http://dx.doi.org/10.1016/j.ejrad.2017.02.026 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
PET/MR imaging of pelvic malignancies Axel Wetter, M.D.1* Johannes Grüneisen, M.D.1
1
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Lale Umutlu, M.D.1
Department of Diagnostic and Interventional Radiology and Neuroradiology,
Corresponding Author:
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*
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University Hospital Essen, Hufelandstraße 55, 45122 Essen
Axel Wetter, M.D.
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University Hospital Essen
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Department of Diagnostic and Interventional Radiology and Neuroradiology
Hufelandstraße 55
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45122 Essen
Tel.: 0049-(0)201-723-84522 Fax: 0049-(0)201-723-1563 Email: [email protected]
Review article
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Highlights Integrated PET/MRI with simultaneous acquisition of PET and MRI is an emerging and promising technique in oncologic imaging Imaging of female and male pelvic oncologic diseases like cervical cancer and
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prostate cancer requires a high soft tissue contrast and make these entities especially suitable for PET/MR imaging
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This review article highlights recent publications of PET/MR imaging in both
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entities
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PET/MR imaging of pelvic malignancies
Abstract Integrated PET/MRI is a new technology which allows simultaneous acquisition of
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positron emission tomography and magnetic resonance imaging data during one examination. The technique appears to be particularly appropriate for oncologic
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imaging of female and male pelvic malignancies, as these entities demand a high soft
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tissue contrast and might be further assessed metabolically with PET. The review
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article highlights recent developments of integrated PET/MRI in pelvic malignancies.
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Introduction Since the first publication of images from a commercial clinical Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) scanner in the year 2008 (1), numerous studies have been performed and published in order to analyze and
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evaluate this new technology in clinical routine (2). A clear advantage of integrated PET/MRI is the inherent possibility to combine the high soft tissue contrast of the MR
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component with the metabolic information of the PET component, derived from the
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utilization of different and specific tracers. Therefore, considerable effort has gone into the evaluation of pelvic malignancies with PET/MRI, as these tumor entities
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require a high soft tissue contrast and might be further distinguished with functional MR imaging methods like diffusion weighted imaging (DWI) and dynamic contrast
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enhanced (DCE) imaging techniques. This review article will focus on the latest developments regarding PET/MRI in female and male pelvic malignancies, notably
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cervical carcinoma and prostate cancer.
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PET/MRI in prostate cancer
Imaging of prostate cancer particularly seems to be appropriate for integrated PET/MRI, as the entity can reasonably be examined only with MRI, where the
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anatomical peculiarities of the prostate gland can properly be assessed in contrast to computed tomography. Furthermore, multi-parametric MR imaging of prostate cancer has become the modality of choice, as the combination of morphological (T2weighted imaging) together with functional imaging (DWI and DCE) examines the tumor as complete as possible and weights the parts of multi-parametric imaging differently. This imaging strategy is expressed by the Prostate Imaging Reporting and Data System Version 2 (PI-RADS v2), which was published in 2015 from the American College of Radiology (3). A substantial component of multi-parametric
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prostate MR imaging is represented by diffusion-weighted imaging, being determined as the dominant sequence for tumor detection of the peripheral zone (3). At present, proton-MR spectroscopy plays only a minor role in prostate MR imaging and has been omitted from the latest PI-RADS classification. Recommended MR sequences
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for prostate cancer imaging are high resolution T2-weighted fast spin echo sequences in axial, coronal and sagittal planes, a diffusions-weighted sequence
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including high b-values and a dynamic contrast enhanced imaging sequence (e.g. a
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T1-weighted VIBE sequence obtained every 7 seconds for 5 to 10 minutes). PET imaging of prostate cancer mainly relies on the utilization of radio-labelled
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choline tracers and 68Ga prostate-specific-membrane-antigen (PSMA), both of them representing different approaches of metabolic imaging in prostate cancer. Both
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radio-labelled choline and PSMA tracers are frequently used in PET/MRI of the
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prostate, as well as for the evaluation of primary prostate cancer and recurrent disease. The rationale of examining primary prostate cancer with integrated PET/MRI
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is to optimize tumor detection by using combined morphologic, functional and metabolic information during one examination. This is possible with the most commercial PET/MRI scanners, as the MR scan and the PET scan are operated
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simultaneously. Up to now, certain studies have been performed, mainly yielding at comparison of the information of combined PET/MRI with that of PET or MRI alone. PET/MRI of prostate cancer with radiolabelled choline PET imaging of prostate cancer with radio-labelled choline mainly utilizes carbon-11 choline or 18F-labelled choline analogs, notably 18F-fluoroethylcholine and 18F fluorocholine (4, 5, 6). Looking at 18F choline as the utilized tracer, a most recently published study using 18F fluorocholine came to the conclusion that the combined information of integrated 18F choline PET/MRI has significantly better sensitivity, Page 5 of 24
specificity, positive and negative predicitive values as well as diagnostic performance than multi-parametric MRI alone (7). In this study, 31 patients were examined with a dedicated PET/MRI scanner before radical prostatectomy and histopathology results served as the gold standard. The authors explained the improvement of diagnostic
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accuracy by use of integrated PET/MRI partly with the complementary information of PET and ADC, especially in low Gleason tumors and concluded that integrated 18F
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choline PET/MRI might be a reasonable imaging modality for initial staging with local
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and whole body PET/MR imaging in the future, after confirmation of its additional value for the detection of local spread and distant metastases. Another most recently
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published study provided an interim analysis of an ongoing prospective clinical trial (8) evaluating the value of fusion 18F fluorocholine PET/MRI for detection of
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significant prostate cancer with image-guided prostate biopsy. On the contrary to the study mentioned before, this study was based on fused images from PET/CT and
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multi-parametric MRI with the inherent disadvantage of the required registration of PET and MR images and thus did not represent a “real” simultaneous or integrated
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PET/MRI. However, the authors found that addition of the PET signal (quantified as SUV mean target-to-background ratio) significantly improved detection of Gleason
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>/= 3+4 prostate carcinomas.
A study from de Perrot et al. published in 2014 (9) investigated the additional value of 18
F fluorocholine PET parameters in addition to multi-parametric MRI for tumor
detection. The results of 23 patients who were undergoing radical prostatectomy after hybrid PET/MRI examination indicated a significantly better tumor detection of PET/MRI than multi-parametric MRI alone in the peripheral zone, whereas there was no advantage of PET/MRI in detection of transitional zone tumors. Logistic regression analysis identified SUVmax and ADC as the strongest parameters in PET/MRI, and
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with absent correlation of these parameters, the authors deduced that SUVmax and ADC might be independent biomarkes. A single center prospective clinical trial investigating fused 18F fluorethylcholine (FEC) PET and endorectal MRI in patients with biopsy proven prostate cancer
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scheduled for radical prostatectomy reported a high sensitivity in detection of the
dominant prostate cancer lesion and also stated a significantly better performance of
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fused PET/MRI than endorectal MRI alone (10). However, the MR protocol mainly
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based on T2 weighted images and did not include a real multi-parametric setting including DWI and DCE, therefore the inferior performance of MR imaging in this
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study should be interpreted with caution. Nevertheless, the high quality of the study design with a clear prospective setting and the excellent gold standard with
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reconstructed whole mount sections of the prostate after radical prostatectomy is a
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strong proponent of combining 18F choline PET and MRI in primary prostate cancer. The quoted studies demonstrate the ability of 18F choline PET/MRI to improve
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detection of tumor foci in primary prostate cancer in contrast to MRI alone. This is in contrast to 11C or 18F choline PET/CT studies, where imaging of primary prostate cancer generally is not recommended and is considered to be inferior as compared to
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MRI (11). The inferior soft tissue contrast of PET/CT and the possibility of consideration of both choline metabolism and high resolution MR imaging might explain the different performance of PET/CT and PET/MRI in primary prostate cancer. Suspected recurrent disease after radical prostatectomy is a major problem in prostate cancer management and needs appropriate clarification. If a rising PSA level occurs after definite treatment of prostate cancer, radio-labelled choline PET/CT has been shown to provide valuable information of the site of recurrent disease and has Page 7 of 24
been judged to improve care in patients with biochemical failure (12). Regarding real integrated PET/MRI for detection of recurrent prostate or lymph n ode disease, the literature is scarce up to now. However, a study that investigated fused 18F choline PET/MRI reported of a significantly higher sensitivity, accuracy and negative
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predictive value than multi-parametric MRI or contrast enhanced CT alone on a lesion based analysis. Patient based analysis, however, did not yield significant
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differences between 18F choline PET/MRI and mpMRI alone. The study population
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was small (21 patients), therefore prospective studies with a larger patient collective are needed to provide substantial information of a potential advantage of integrated
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PET/MRI in detecting recurrent disease in biochemical recurrent prostate cancer. An example of a 18F fluorocholine PET positive primary prostate carcinoma and a 18F
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fluorocholine PET positive bone metastasis is shown in figure 1.
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PET/MRI of prostate cancer with 68Ga PSMA
Prostate-specific-membrane-antigen (PSMA) is a membrane bound protein in
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prostate cancer cells, but is at a lower level also expressed for example in the brain or salivary glands. For PET imaging, particular kind of PSMA ligands are used, of whom the most commonly used is 68Ga PSMA-HEBD-CC (full name Glu-NH-CO-NH-
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Lys-(Ahx)-68Ga-(HBED-CC)) (13). The first study of integrated PET/MRI utilizing this tracer was published in 2014 and demonstrated feasibility (14). From 20 patients with biochemical recurrence after definitive treatment of prostate cancer examined, all MRI examinations from integrated PET/MRI were of diagnostic quality. Moreover, PET/MRI could clarify four ambiguous PET/CT findings in three patients. However, this study also reported of an extinction of the PET signal in the scatter corrected PET images of integrated PET/MRI around the kidneys and urinary bladder, the socalled “halo”, in a significant proportion of patients. This “halo” led to significant
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underestimation of SUVs in altogether 7 lesions in 3 patients and was explained by the authors with the unstable scatter correction of integrated PET/MRI systems. In order to prevent false negative results, all PET images from integrated 68Ga PSMAHEBD-CC PET/MRI should be visualized and inspected without scatter correction
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(14). Further recommendations are sufficient hydration, voiding immediately before examination and forced diuresis induced by intravenously administered furosemide to
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minimize the halo artifact. Recently, Eiber et al. evaluated the diagnostic performance
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of 68Ga PSMA-HEBD-CC integrated PET/MRI in comparison to multi-parametric MRI and PET alone (15). The study included 66 consecutive patients, of whom 53 were
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finally eligible for retrospective evaluation. Gold standard was histological sextant based examination of the prostate gland. The study demonstrated that PET/MRI as
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well as PET was superior over multi-parametric MRI on a patient-based analysis as well as on a sextant based analysis. Diagnostic accuracies for prostate cancer
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detection, provided as areas under the curve from a ROC analysis were significantly higher for PET and PET/MRI than for mpMRI alone. No significant differences of the
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AUC were found between PET and PET/MRI. For prostate cancer localization, PET/MRI reached the highest AUC, followed by PET and mpMRI, respectively. The authors concluded that simultaneous 68Ga PSMA-HEBD-CC PET/MRI increased
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diagnostic accuracy in prostate cancer detection and localization and recommended realization of prospective studies to further evaluate PET/MRI in prostate cancer. Among possible study limitations, the authors addressed that only b-values until 800 s/ mm2 were employed, indicating that the employed DWI sequence might be diagnostically less conclusive as if higher b-values would have been used. Examples of 68Ga PSMA PET positive primary prostate carcinomas, local recurrences and lymph nodes are shown in figures 2 – 6.
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To summarize the results of the actual studies regarding PET/MRI in prostate cancer, the method implies a high potential to further improve prostate cancer detection and localization in patients with primary prostate cancer when compared to multiparametric MRI. This might be especially valuable for patients with clinical suspected
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prostate cancer who are scheduled for a second biopsy after the first was negative. Regarding suspected lymph node or bone metastases, which is a major issue in
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methods of CT, PET/CT and bone scintigraphy is necessary.
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prostate cancer patient care, further evaluation and comparison with the standard
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PET/MRI in cervical cancer Despite well-established screening and prevention methods, cancer of the uterine cervix is considered both the third most common cancer type as well as cause of
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cancer-related death in women worldwide (16). Once diagnosed, the prognosis
mainly depends on the stage of the cancer at initial diagnosis. While survival rates of
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microscopic forms of cervical cancer may be as high as 100%, survival rates of stage
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3 and/ or higher are shown to decrease to less than 40% (17). With curative options such as surgery and concurrent chemo-radiotherapy being limited to small local
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tumors (4cm; stages IA, IB1, IIA1), correct high-quality assessment of local tumor extent as well as of lymphonodular and distant metastatic spread is imperative for
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optimized patient management and therapy planning (18). While the reference
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standard for staging still involves clinical examination under anesthesia combined with cystoscopy, proctoscopy, sigmoidoscopy and biopsy (19), current guidelines
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such as the revised FIGO (Federation of Gynaecology and Obstetrics) staging system seize the importance of high-quality imaging diagnostics in recommending the application of cross-sectional imaging for correct tumor staging, particularly
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stressing the superiority of MRI for assessment of local tumor extent (20-22). Based on its inherently high soft-tissue-contrast as well as high spatial resolution imaging capacity, MR imaging has been shown to provide accurate information on important prognostic as well as therapy-crucial factors, such as tumor size, parametrial and pelvic sidewall invasion (23,24), hence it is recommended as an adjunct to clinical assessment. While MRI has been shown superior for evaluation of the local tumor extent (over other cross-sectional imaging modalities), molecular imaging, by means of 18F-FDG-PET/CT, has been demonstrated to enable superior (lymph node) staging, overall restaging and treatment monitoring of gynaecological malignancies Page 11 of 24
(25). Numerous studies underlined the added value of the assessment of metabolic features of lymph nodes, facilitating higher sensitivity and specificity rates for lymph node staging, particularly in patients with locally advanced cervical cancer when comparing PET/CT to MRI (21,26). Pooled sensitivity and specificity rates of PET/CT
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were shown to be as high as 82 and 95% over 56 and 91% in MRI (27). Therefore, PET/CT is considered an accurate imaging alternative to surgical lymph node
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dissection in advanced tumor stages, as micro-metastases may be missed due to
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deficient increase of tracer uptake (26-28). Although FIGO staging does not cover lymphadenopathy, it has been shown that exclusion / detection of lymph node
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metastases displays an important factor for patient prognosis as well as treatment planning (29). Considering the strength of MRI for local staging and the strength of
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PET/CT for lymph node and whole-body staging, the combined analysis of morphologic and metabolic parameters may help to leverage staging of gynaecologic
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malignancies (Figure 7). Until recently, investigators tried to overcome the lack of integrated PET/MR systems, by performing subsequent PET/CT and MR scanning
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and retrospective data fusion. While this is a commonly applied approach for rigid application fields, such as brain imaging, the assessment of structures of the female pelvis demands simultaneous data acquisition, as physiologic peristaltis of the bowel
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system as well as diverging bladder filling may significantly impair correct coregistration of subsequently acquired metabolic and morphologic data. Hence, the recent introduction of integrated PET/MRI scanner systems may help to diminish these problems of correct merging of metabolic and morphologic information and enable a valuable conjunction of the best of both imaging modalities. Although limited, initial studies have reported promising results on the application of integrated PET/MRI for primary staging and restaging of patients with gynaecological malignancies of the female pelvis (30, 31). Grueneisen et al were one of the first to
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report on the feasibility and diagnostic value of integrated PET/MRI for staging of primary cervical cancer. The study comprises a rather small patient cohort of 27 patients with histologically proven cervical cancer and reveals its high diagnostic competence for primary staging in facilitating correct determination of the T-stage in
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85% of the patients as well as sensitivity, specificity and diagnostic accuracy rates for the detection of nodal positive patients of 91%, 94% and 93%, respectively. Apart
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from the promising results for T and N-staging, which should be considered
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preliminary due to the small patient cohort, the study revealed further encouraging information regarding correlations between PET and MRI derived functional
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parameters for grading and tumor size (32). The added value of the metabolic component of PET/MRI was also taken up in another study by Brandmeier et al (33).
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Comparable to a study by Grueneisen et al,. Brandmeier et al investigated the correlation between PET and DWI parameters, showing that the mean SUVmax and
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ADC min of primary tumors and metastases showed a significant inverse correlation, whereas the correlation in recurrent lesions lacked to merit significance, which is
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probably caused by the altered biology of tumor recurrences (32, 34). These results underline the diagnostic potential of simultaneous multi-parametric PET/MRI for the assessment of non-invasice functional biomarkers, demonstrating the strong
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correlation between tumor metabolism and increased cellularity in (primary) cervical cancer lesions (Figure 8). Apart from primary local cancer staging initial investigations have also revealed the diagnostic potential of integrated PET/MRI for radiation planning as well as therapy monitoring. Up to current status, PET/CT has been well-established to define the gross tumor volume for radiation therapy (34, 35). Nevertheless, based on the improved delineation of the local tumor extent in MRI, PET/MRI may bear the potential to replace PET/CT and enable a more precise delineation of the tumor extent combined with the metabolic information and facilitate
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improved target therapy (35). In more advanced tumor stages chemotherapy is commonly applied to reduce the tumor volume. However, while MRI allows for an excellent assessment of the primary tumor, post-therapeutical changes after chemoand/ or radiotherapy may impair the correct differentiation between residual tumor
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and post-therapeutical changes. This may be another important diagnostic application field, which may benefit from the combined analysis of metabolic and
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morphologic tumor features (Figure 9). Apart from its applications for local tumor
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assessment, therapy monitoring and radiation treatment planning, integrated PET/MRI bears the potential for another important application field, by means of
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whole-body staging and restaging. Within the last few years, numerous studies have demonstrated its high diagnostic potential for numerous tumor entities (37-39). This
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may also apply for staging patients with primary and recurrent cervical cancer (30, 31). Various studies investigated the diagnostic competence of integrated PET/MRI
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compared to MRI alone as well as compared to PET/CT. The overall conclusion is that integrated PET/MRI facilitates superior whole-body staging when compared to
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MRI alone and comparable results to PET/CT, while enabling a significant reduction of the applied ionizing radiation (30,31). After initial studies demonstrated its diagnostic competence, yet requiring long examination times, more recent studies put
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the focus on protocol optimization to facilitate shorter overall examination times, while preserving the high diagnostic competence (40, 41). In summary, it is well deserved to conclude that the past 5 years of successful introduction of integrated PET/MRI into research and clinical imaging have demonstrated its high diagnostic potential for simultaneous investigations of the morphologic and metabolic features of malignancies of the female and male pelvis, comprising local and whole-body staging, exclusion of tumor relapse as well as therapy monitoring. Page 14 of 24
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Figure legends Figure 1 69 year old patient with a histological proven prostate carcinoma who exhibits a
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choline-positive prostate carcinoma of the left transitional and peripheral zone and choline-positive bone metastases.
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A) T2 weighted image in axial orientation shows a large hypo-intense mass of the
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left transitional and peripheral zone and delineation of a hypo-intense area in the right pubic bone (arrows).
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B) Fused 18F Fluorocholine PET/MRI demonstrates intense tracer uptake of the
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prostate carcinoma and also of the metastasis in the right pubic bone.
Figure 2
Ga PSMA PET/MR images from a 59 year old patient after radical prostatectomy.
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68
examination.
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PSA level was slowly rising after operation to a level of 0.55 ng/ ml at the time of
A) T1-weighted fat-saturated image with contrast in axial orientation depicts a small lymph node just beside the left external iliac artery (arrow). From the
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contrast enhanced images, it was equivocal whether the lymph node was benign or malignant, as it was small with a distinct fatty proportion.
B) However, fused PET/MR image demonstrated pronounced tracer uptake of the lymph node, making it highly suspicious to be a lymph node metastasis.
Figure 3 Multi-parametric 68Ga PSMA-PET/MRI assessment of a biopsy proven primary prostate carcinoma of the left transitional and peripheral zone in a 81 year old
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patient. Patient was referred for initial staging of the recently diagnosed cancer. Distant metastases could not be confirmed with PET/CT and PET/MRI. A) T2-weighted fast spin echo sequence with 3 mm slice thickness depicts a large hypo-intense tumor of the left peripheral zone.
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B) Dynamic-contrast-enhanced imaging of the tumor shows early enhancement of the tumor.
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C) ADC map from Diffusion-weighted imaging with hypo-intense delineation of
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the tumor.
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D) Fused T2 68Ga PSMA PET images with strong tracer uptake of the tumor.
Figure 4
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59 year old patient with slowly rising PSA level up to 7.1 ng/ml and suspected prostate carcinoma. T2 weighted MR imaging demonstrates pronounced hyperplastic
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remodeling of the prostate gland without a clear tumor-suspicious finding. However, a doubtful T2 hypo-intense lesion was found in the left peripheral zone of the prostate.
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DWI did not contribute to further clarification due to a large susceptibility artifact. Ultrasound guided saturation biopsy localized prostate cancer only in the left dorsal area as indicated by PET/MRI.
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A) T2 weighted high resolution T2 weighted image at mid-gland level demonstrates pronounced changes typical for benign prostatic hyperplasia.
B) T2-weighted high resolution image between mid gland and apex depicts a faint hypo-intense small lesion in the left transitional zone. C) Fused 68Ga-PSMA-PET/MR image demonstrates pronounced tracer uptake of the lesion. Saturation biopsy confirmed prostate cancer at this level of the prostate gland.
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Figure 5 Multi-parametric 68Ga PSMA PET/MR Images from a 67 year old patient with a rising PSA level after radical prostatectomy. Patient was referred to the PET/CT and PET/MRI unit for further clarification. PSA level reached 1.1 ng/ml. In the further
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course the Patient was scheduled for radiation therapy of the prostate bed. A) T2 weighted image in axial orientation demonstrates a hypo-intense mass left
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laterally from the vesico-urethral anastomosis.
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B) Dynamic contrast enhanced MR imaging shows this lesion early enhancing. C) Diffusion-weighted image with high b-value (1000s/mm2) depicts the lesion
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hyper-intense, indicating a diffusion restriction of the lesion.
D) Fused PET/MRI image with a strong tracer uptake of the lesion, which was
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diagnosed as recurrent disease in the prostate bed.
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Figure 6
65 year old patient with a rising PSA level after radical prostatectomy. At 68Ga-
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PSMA-PET/MRI examination, PSA reached 0.86 ng/ml. PET/MRI revealed a small lymph node just medially from the pectineus muscle. After PET/MRI, lymphadenectomy was performed and confirmed a single lymph node metastasis.
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A) T1-weighted fat-saturated image after administration of a paramagnetic contrast agent depicts a small lymph node just medially the pectineus muscle, which was overlooked in the morphological images.
B) Fused 68Ga PET/MR image demonstrates strong tracer uptake in the lymph node, which was later histologically confirmed by lymphadenectomy.
Figure 7
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Images of a 47 years-old-patient diagnosed with primary cervical cancer (squamous cell carcinoma). Post-contrast T1w VIBE (A) and T2 TSE images (B) show the manifestation of the tumor confined to the uterine cervix (Tumor stage IB2) which reveals restricted diffusion (D,E) as well as pathologic glucose metabolism after
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image fusion in PET/MRI (C,F).
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Figure 8
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Mutiparametric imaging of a patient with primary cervical cancer. Integrated PET/MRI facilitates the simultaneous assessment of morphological (T2 TSE, image A9,
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metabolic (B), perfusion (C) as well as diffusion features of the tumor.
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Figure 9
Images of a 33 years-old female patient with primary cervical cancer. Prior to the
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initiation of neoadjuvant chemotherapy. MR images (A, T2 TSE; B, T1 VIBE p.c) show a tumor manifestation at the uterine cervix infiltrating the vaginal rim as well as
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the uterus which reveals pathologic glucose metabolism after image fusion in PET/MRI (C, PET/MRI). After completion of initial treatment no focally increased tracer uptake is detectable, indicating complete resection (F, PET/MRI). However, on
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MR images (D, T2 TSE; E, T1 VIBE p.c) there is still suspicion of a tumor residue. After surgical resection, no tumor tissue could be verified histopathologically, confirming the diagnosis based on PET/MRI.
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