PET/MR imaging of neoplastic and inflammatory lesions Catalano, Onofrio Antonio

University of Groningen

PET/MR imaging of neoplastic and inflammatory lesions Catalano, Onofrio Antonio

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Chapter 5

Colorectal cancer staging: comparison of whole- body PET/CT and PET/MR

Catalano OA, Coutinho AM, Sahani DV, Vangel MG, Gee MS, Hahn PF, Witzel T, Soricelli A, Salvatore M, Catana C, Mahmood U, Rosen BR, Gervais D.

Abdom Radiol (NY). 2017 Apr;42(4):1141-1151

Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging (O.A.C, C.A.M., B.R.R., T.W., M.G.V.), and Biostatistics Center (M.G.V.), Massachusetts General Hospital, Harvard University Medical School, Boston, Mass;

Department of Radiology, (O.A.C., G.M.S., D.V.S., P.F.H., D.G.), Massachusetts General Hospital, Harvard University Medical School, Boston, MA;

Department of Diagnostic Imaging (A.S.), University Parthenope, Naples, Italy.

Department of Radiology, (M.S.), SDN-IRCCS, Naples, Italy

Abstract

Purpose: Correct staging is imperative for colorectal cancer (CRC) since it influences both prognosis and management. Several imaging methods are used for this purpose, with variable performance. Positron emission tomography-magnetic resonance (PET/MR) is an innovative imaging technique recently employed for clinical application.

The present study was undertaken to compare the staging accuracy of whole-body positron emission tomography-computed tomography (PET/CT) with whole-body PET/MR in patients with both newly diagnosed and treated colorectal cancer.

Methods: Twenty-six patients, who underwent same day whole-body (WB) PET/CT and WB-PET/MR, were evaluated. PET/CT and PET/MR studies were interpreted by consensus by a radiologist and a nuclear medicine physician. Correlations with prior imaging and follow-up studies were used as the reference standard. Correct staging was compared between methods using McNemar's Chi square test.

Results: The two methods were in agreement and correct for 18/26 (69%) patients, and in agreement and incorrect for one patient (3.8%). PET/MR and PET/CT stages for the remaining 7/26 patients (27%) were discordant, with PET/MR staging being correct in all seven cases. PET/MR significantly outperformed PET/CT overall for accurate staging (P = 0.02).

Conclusion: PET/MR outperformed PET/CT in CRC staging. PET/MR might allow

accurate local and distant staging of CRC patients during both at the time of diagnosis

and during follow-up.

Intrduction

Colorectal cancer (CRC) is one of the most clinically relevant cancers with 142,820 estimated new cases in the US in 2013. Additionally, it represents the fourth most common cause of cancer death worldwide, and it has been responsible for 51,516 cancer deaths in the U.S. in 2012, the second overall [1–3].

Correct staging is imperative for CRC. Overall survival is strictly correlated with stage at presentation: the 5-year survival rate drops dramatically from stage I (93%) to stage IV (8%)[1]. Several treatment options are available, including surgery, neoadjuvant chemotherapy with or without radiation therapy, systemic chemotherapy, and palliation, which need to be tailored by several factors, the most important being clinical stage.

Moreover, treatment costs increase between 1.4 and 2.33 times from early to late stage of the disease[4–7].

Different imaging methods are currently used for staging and re-staging CRC, including morphologic imaging like computed tomography (CT), magnetic resonance imaging (MR), and metabolic imaging, like positron emission tomography (PET) with ¹⁸ F- fluorodeoxyglucose (FDG). These methods have variable performances in lesion detection and staging, further influenced by the local or distant aim of staging [8–12]

[13–18].

PET/CT relies on the extremely high sensitivity of PET to the picomolar accumulation of FDG and the anatomic layout of CT for their allocation. This explains its superior performance in the search for distant metastases [14,19–21], with sensitivity as high as 94% in the per-patient detection of malignant liver lesions [14] and an accuracy of more than 90% in the detection of recurrent disease [19]. However, anatomic allocation of FDG avid foci might sometimes be challenging on PET/CT due to the asynchronous acquisition of the PET data and CT images, and to the low soft tissue contrast ratio and low contrast to noise ratio of CT. This explains some challenges faced by PET/CT, for example in the setting of smaller than 10 mm liver lesions, subcapsular liver lesions, peritoneal metastases, and in the case of apparently nonspecific intestinal uptake of FDG [14,19].

On the other side, MR is preferred to CT for local staging of CRC due to its higher soft-

tissue ratio and contrast to noise ratio. Also, due to the resultant higher sensitivity for detection of smaller liver lesions, is the preferred modality for assessment of hepatic metastases, including those in the subcapsular areas [14].

Given the above-mentioned advantages of MR over CT and the high sensitivity of PET, the advent of hybrid scanners combining PET and MR (PET/MR) is extremely appealing for investigation in CRC staging[22]. PET/MR seems not inferior to contrast- enhanced (CE) CT [23] and PET/CT [24–26] in oncologic imaging, including CRC [27].

However, despite the clinical approval of PET/MR dating back to 2012, there is still a paucity of studies comparing PET/MR with PET/CT. The purpose of the present study was to compare the staging performance of whole-body PET-CT with PET-MR in patients with naive and treated colorectal cancer.

Method and Materials

Patients

This retrospective study was approved by the institutional review board and was compliant with the Health Insurance Portability and Accountability Act. All the patients who underwent PET/MR signed an informed consent for possible future utilization of the data in oncologic imaging research, including retrospective comparative staging with PET/CT.

The study included consecutive adult patients with the diagnosis of CRC, who underwent same day contrast-enhanced PET/CT and contrast-enhanced PET/MR imaging. Other inclusion criteria were: (a) age older than 18 years, (b) less than 180 minutes of delay between FDG injection and the PET/MR scan, (c) at least 12 months follow-up data and/or pathology confirmation. Exclusion criteria were: (a) pregnancy, (b) blood glucose levels greater than 140 mg/dL (7.77 mmol/L), and (c) contraindication to MR imaging.

PET/CT acquisition protocols

All patients fasted for at least 6 hours before scanning and peripheral blood glucose

levels were measured immediately before FDG injection (OneTouch Vita; LifeScan,

Milpitas, Calif). PET/CTs were acquired 60 minutes after ¹⁸ F-FDG injection (mean dose 4.44 MBq per kilogram of body weight; range: 370–400 MBq) on a dedicated 64- detector time-of-flight PET/CT scanner (Gemini TF; Philips, Best, the Netherlands).

PET/CT was acquired, according to the manufacturer recommendations, from the mid thighs to the vertex, before and after the injection of intravenous contrast medium. Both diagnostic unenhanced and contrast-enhanced (CE) images were acquired with shallow and smooth free breathing. PET data were automatically corrected for using CT data. Iodinated contrast (iomeprol, Iopamiro 370; Bracco Imaging, Milan, Italy) was injected intravenously at a rate of 2 mL/sec, at a dosage of 80 mL in patients ≤80 kg and 100 mL in those weighting >80 kg. CECT images were acquired with a bolus care function in the arterial, portal and delayed phases of contrast enhancement. Chest and upper abdomen images were acquired with breath hold. Total acquisition time was 18 minutes ± 9 minutes.

PET/MR acquisition protocols

A Biograph mMR scanner (Siemens Healthcare, Erlangen, Germany) was used for the acquisition of the PET/MR studies, with a 16-channel head and neck surface coil and three or four 12-channel body coils, depending on the height of the patient. Total imaging matrix technology was used to combine the coils into a single multichannel whole-body coil. Our protocol includes co-acquired MR sequences that are run simultaneously with PET regardless of the operative status of the patient, and additional dedicated MR sequences, performed after completion of the PET acquisition, which were chosen on the basis of the operative status.

Co-acquired PET/MR sequences, run in all patients, were: whole body (WB) coronal

T1-weighted (T1w) two-point Dixon volume-interpolated breath-hold examination

(VIBE); WB coronal STIR; axial WB diffusion-weighted imaging (DWI); and WB axial

T2-weighted (T2w) HASTE. Such sequences were acquired from the mid thighs and

moved towards the skull. Patients were instructed to breath in a shallow and smooth

manner. Upper abdomen and thoracic sequences were acquired during expiration

breath holding. Attenuation correction was performed automatically with maps

generated from the two-point Dixon sequence. An automatic correction was performed

to account for the delay between the time of FDG injection and the time of PET data acquisition for each bed position.

After completion of the PET, in the case of non-operated rectosigmoid cancers and/or clinical suspicion of residual rectosigmoid cancer, T2 fast spin echo high-resolution triplanar pelvic sequences were acquired, followed by contrast enhanced WB T1w axial and coronal GE sequences; in the case of operated patients with no clinical suspicions of residual tumors in the pelvis, a dedicated upper abdominal protocol included axial T2w fast spin echo fat saturated, axial T1w dual gradient echo, coronal T2w HASTE, dynamic contrast enhanced T1w axial GE sequences on the upper abdomen, followed by contrast enhanced WB T1w axial and coronal GE sequences. 0.1 mmol/kg (0.5 mmol/mL) of gadopentate dimeglumine (Magnevist; Bayer Pharma, Berlin, Germany) were injected intravenously at a rate of 3 mL/sec followed by the same volume of saline.

Average scan time was 61 minutes ± 18 minutes.

Image registration, fusion and evaluation

A dedicated workstation (Extended Brilliance Workstation; Philips) was used for the co- registration, fusion, and analysis of the PET/CT images, which were further evaluated at a picture archiving and communication system (IDS7; Sectra, Linkoping, Sweden).

The same PACS and a dedicated workstation (Syngo.via; Siemens Healthcare, Erlangen, Germany) were used for fusion, analysis, and evaluation of the PET/MR images.

Two readers, one radiologist (OAC) with 17 years of experience in MR and one nuclear medicine physician (AS) with 33 years of experience in nuclear medicine, evaluated together by consensus the images. PET/CT and PET/MR scans were separately evaluated at least six weeks apart. The stage was assigned according to TNM classification [28]. Readers were aware of the diagnosis of treated or untreated CRC but were blinded to prior studies and to the other modality. All the data was recorded in spreadsheets, and the TNM stages of both methods were compared.

Pathology served as the standard of reference when available; otherwise, correlation

with prior imaging studies, with >12months imaging follow-up and with clinical data,

was performed. In particular we relied on reduction in size and/or of FDG uptake after

treatment or in increase in size and/or of FDG uptake of lesions, regardless of treatment, as confirmation of recurrence or metastatic nature of a lesion. We relied on reduction both in size and in FDG uptake, if lesions were untreated, as exclusion criteria of recurrence/metastatic nature of a lesion.

Statistical analysis

Correct staging was compared between methods using McNemar’s chi-square test.

And a value of p=0.05 was chosen for statistical significativity.

Results

Our population included 26 patients (11 female, 15 male), with a mean age of 61.2 (±12.9) years. Fourteen were untreated CRC patients who underwent initial staging, and the other 12 were treated CRC patients who underwent PET/CT and PET/MR for restaging.

Twenty-six patients were each staged using both PET/MR and PET/CT. Compared to the true stage, the two methods were both in agreement and correct for 18/26 (69%) patients, and both in agreement and incorrect for 1/26 (3.8%) patient. In particular, of the 18 patients where both PET-CT and PET-MR were concordant and correct, 12 patients were in stage IV (figure 1), 2 patients had recurrence of the disease, 2 patients had stage II and 2 patients had no signs of recurrence. PET-CT and PET-MR were concordant but both incorrect in 1/26 patient whose stage was III at both PET-CT and PET-MR but II at pathology.

PET/MR and PET/CT stages for the remaining 7/26 patients (27%) were discordant, and for all of them PET/MR stage was correct, and PET/CT was incorrect (Table 1).

Based on McNemar’s test, PETMR significantly outperformed PETCT for correct staging (McNemar test, P=0.02).

Four of these seven discordant patients were correctly upstaged by PET/MR, compared to PET/CT:

One patient without signs of recurrent disease on PET/CT, had peritoneal implants on

PET/MR, that were miss-interpreted as non-specific intestinal uptake on PET/CT.

However, theirs circumscribed appearance and restricted diffusion, along with matching of the gadolinium enhancement with FDG uptake on PET/MR, allowed the diagnosis to be made.

One patient, erroneously classified stage II on PET/CT, had regional lymphadenopathy detected on PET/MR (stage III).

Two patients, classified on PET/CT as stage III, PET/MR found non-regional retroperitoneal lymphadenopathy (stage IV). The lymphadenopathy that was not demonstrated on PET/CT displayed restricted diffusion on ADC maps (<1000x 10 ^-

6 mm ² /s), heterogeneous enhancement, and intermediate signal intensity on STIR (Figure 2), allowing PET/MR to make the diagnosis of metastatic lymphadenopathy.

Two of seven discordant patients had suspected residual/recurrent disease in the post surgical bed on PET/CT; however, PET/MR demonstrated prostatic inflammation in one and post-surgical fistula in the other case (Figure 3).

In the third and last discordant case, non-regional lymphadenopathy on PET-CT (stage IV), was demonstrated to be reactive on PET/MR, due to the high ADC values, allowing the classification as stage III, as confirmed at pathology.

Discussion

Imaging plays a pivotal role in patient management trough local and distal staging of un-treated CRC and re-staging of treated ones. CT, MR, and PET-CT are the most commonly employed imaging techniques used for this purpose, with variable performances. For local staging, reported sensitivity, specificity and accuracy are 78- 79%, 63-78%, and 66-73% respectively for CT, and 82-86%, 76-77%, and 74-82%

respectively for MR, and 75-90%, 42-76%, and 68-85% respectively for PET/CT [8–

12]. For distal staging, reported sensitivity, specificity and accuracy are 58-89%, 87- 94.9%, and 52-77% respectively for CT, 80-85%, 92.5-99%, and 82-98% respectively for MR, and 66-86%, 67-97.2% and 64-83% respectively for PET-CT [14–18].

An ideal imaging technique should provide a one stop-shop assessment of both loco- regional extension and distal status.

PET/CT, despite its high performance in the assessment of distal spread of disease,

due to the low soft tissue resolution and low signal and contrast to noise ratios of CT, is limited in the assessment of loco-regional extension, particularly in the settings of sigmoid and rectal cancers [12]. Moreover anatomic allocation of FDG avid foci might be challenging, due to the asynchronous acquisition of the PET data and CT images, with resultant limitations in the setting of <10mm liver metastases and of peritoneal implants [14,29,30].

On the other side, MR, due to its higher soft-tissue and contrast to nose ratios, and its superiority in local staging of CRC, and in assessment of <10mm liver lesions and of peritoneal implants, might potentially further help PET both in local and distal staging [14,30]

In the present study, PET/MR proved to be more accurate than PET/CT in the initial staging and restaging of patients with CRC. Both methods agreed and were correct in 18/26 (69%) of the cases and agreed and were both incorrect in 1/26 (3.8%) of cases.

Disagreements were noted in 7/26 (27%) of patients: four patients were correctly upstage by PET/MR compared to PET/CT that missed peritoneal carcinomatosis in one case and lymphadenopathy in three. Three patients were correctly down-staged by PET/MR that ruled out residual/recurrent disease in two and excluded non-regional lymphadenopathy in one. Both techniques falsely upstaged (stage III) one patient whose regional lymphadenopathy was negative at pathology (stage II). Similarly to our findings, in a cohort with a high rate of stage IV disease patients, Lee et al. (2015) [27]

reported a high accuracy of PET/MR with pathology as standard of reference. This was confirmed in other series of cases [26].

The superior soft tissue contrast of MR, and the availability of multiple MR sequences, when compared with CT, might enable better assessment of loco-regional extension of recto-sigmoid cancer, including assessment of the distance from the mesorectal fascia, involvement of adjacent anatomic structures, and evaluation of the soft tissue structures in the pelvis and perineum [31,32] In our study this enabled better allocation of areas of FDG avidity and improved soft tissue resolution, allowing the diagnosis of prostatic inflammation and rectal fistula in 2 cases that were misled by the CT part of the PET/CT study.

DWI, along with the resultant ADC maps, and with T2-weighted and post Gadolinium

signal intensity similarities between the primary cancer and the suspected metastases, was of special help to PET/MR in the assessment of lymphadenopathy and of peritoneal implants. In fact, this allowed identifying ADC restricted lymphadenopathy, not evident in PET/CT due to a short axis <10mm, with resultant upstaging of three patients. On the other hand, the non-restricted ADC values and the intrinsically high T2 signal, along with the reduced FDG uptake on PET/MR, allowed to correctly downstage to stage III, a patient otherwise classified as stage IV on PET-CT due to enlarged non- regional lymph nodes that proved reactive at biopsy.

In our evaluation we relied on the combined assessment of all the MR sequences along with the FDG uptake both for local and distal staging/re-staging. This approach is similar to that pursued by others that have reported improved performance of PET/MR when DWI were assessed in conjunction with other pulse sequences like, for example, T1weighted post gadolinium-enhanced images. This was especially useful for the assessment of small lesions and in the post-treatment follow-up of liver metastasis, where FDG-PET loses sensitivity as well [25,27,31–34]. These dedicated abdominal sequences helped in the proper differentiation of abdominal lesions in our present manuscript as well.

In our study PET/MR provided a different and accurate staging in 27% of patients, compared to same day PET/CT. PET/MR outperformed PET/CT by providing better evaluation of the soft tissues of the pelvis and perineum, that allowed characterizing areas of FDG uptake as anorectal fistula and prostatitis. This keeps in line with other studies that demonstrated the advantages of the higher soft tissue resolution of PET/MR compared to PET/CT that also helped better identification of perirectal implants and loco-regional infiltration [25].

PET/MR was also more accurate than PET/ CT while evaluating lymphadenopathy,

due to the restricted ADC values, as ascertained also in previous studies [24]. Previous

studies remark the improved detection of liver metastases by PET/MR [23,26]. This

was not observed in our study, where most of the metastatic lesions in the liver were

correctly detected by both methods. However this might be explained by the small size

of our population.

The study with the highest number of patients with CRC investigated with PET/MR (N

= 51) was reported by Kang et al. (2016) [23]. While comparing PET/MR with contrast- enhanced CT (CECT), which is the preconized staging procedure by the National Comprehensive Cancer Network (NCCN) guidelines, the authors reported potential treatment changes in 21% of cases when using PET/MR, despite the acknowledged reduced sensitivity for lung nodules when compared to CECT. The changes in treatment planning were related to the detection of liver metastases, local tumor recurrence and exclusion of disease activity in other liver lesions or in postoperative fibrotic tissue. This highlights an outstanding impact of PET/MR in comparison to an established technology such as CECT. Nevertheless, the authors did not compare this new technique against a state-of-the-art PET/CT protocol, which could have increased significantly the sensitivity of CECT alone.

Finally, Brendle et al. (2016) compared different imaging strategies for CRC staging and restaging. Even though without statistical significance, the overall accuracy of the combination of PET/MR and DWI was slightly superior to PET/CT. When comparing PET/MR without DWI with PET/CT, overall accuracy was almost the same in both methods [26]. Our data substantially agree with previous studies, suggesting that PET/MR is superior to PET/CT in the local and distal evaluation of CRC, despite some drawbacks of MR imaging like longer scanning time.

Specific MR limitations, such as spatial resolution, and the presence of artifacts, such as those due to motion or susceptibility, were not an important issue in our work. Small lung nodules are specifically difficult to detect with MR due to their low signal intensity in relation to the adjacent lung tissue. However in a study by Chandarana et al the sensitivity of PET/MR was not disappointing. They demonstrated a sensitivity of 70.3%

for all nodules, 95.6% for FDG-avid nodules, and 88.6% for nodules ≥5mm in diameter.

Moreover, it is unclear if the lack of visibility of lung nodules less than 6mm bear clinical implications [24,35].

Also, Paspulati et al. (2013) highlighted that a PET/MR protocol without specific bone- marrow sequences could miss bone infiltration, as seen in one patient of their cohort.

Our protocol includes sequences that are tailored also to assess bone marrow [25].

Our manuscript has several limitations, first of all the small size of our sample. It is,

however, the biggest cohort to our note of CRC patients evaluated by same day contrast enhanced state-of-the-art PET/MR and PET/CT. Second, the retrospective nature of the study, as well as performing PET/CT consistently before PET/MR might represent a source of bias. Some authors relate that the delayed PET images of the PET/MR studies could have a higher lesion-to-background rate in malignant lesions and favor this methodology in comparison to PET/CT. However, there is no clear consensus whether this has a crucial role in final diagnostic performance of PET images [36–38].

In summary, we propose that PET-MR imaging might allow accurate local and distant

staging of CRC patients during initial diagnosis and follow-up. In our cohort, this

technique outperformed PET/CT in local staging and in distant assessment as well.

Table 1

Patients demographic, clinical and imaging characteristics

Patient

status Sex Age

Result of the PET/MR x

PET/CT comparison

PET/MR

staging# PET/CT

staging# Description of the discordant findings Untreated M 43 UPSTAGED by

PET/MR 4a 3c Non regional lymph

node found in PET/MR only.

Untreated F 67 UPSTAGED by

PET/MR 3 2 Regional lymph node

found in PET/MR only Untreated M 42 UPSTAGED by

PET/MR 4 3

Non regional lymph node found in PET/MR only Post-

treatment F 30 UPSTAGED by

PET/MR 4 0

Peritoneal implants, misdiagnosed as nonspecific intestinal

uptake on PET/CT Post-

treatment M 65 DOWNSTAGED

by PET/MR 0 Recurrenc

e

Prostatic inflammation misinterpreted as recurrence on PETCT

Post-

treatmnt M 57 DOWNSTAGED

by PET/MR 3 4

Non-regional lymphadenopathy, reactive at PETMR as demonstrated by high

ADC values Post-

treatment M 31 DOWNSTAGED

by PET/MR 0 Recurrenc

e

Post-surgical fistula misinterpreted as recurrence on PET/CT Untreated F 48 WRONGLY

STAGED BY

BOTH 2 2 Reactive regional

lymph nodes at pathology

Untreated M 73 No changes 4 4

Post-

treatment F 67 No changes 4 4

Post-

treatment M 63 No changes 0 0

Post-

treatment M 82 No changes 4 4

Post-

treatment F 64 No changes 4 4

Post-

treatment F 77 No changes 0 0

Post-

treatment M 60 No changes Recurrenc

e Recurrenc

e

Untreated M 48 No changes 4 4

Untreated F 73 No changes 4 4

# Staging referred as "0"means no sign of active disease. PET: positron emission tomography; M:

Male; F: Female; MR: magnetic ressonance imaging; CT: computed tomography

Untreated M 55 No changes 4 4

Untreated M 49 No changes 2 2

Untreated F 54 No changes 2 2

Post-

treatment M 66 No changes 4 4

Untreated F 58 No changes 4 4

Untreated M 79 No changes 4 4

Post-

treatment M 65 No changes 4 4

Post-

treatment F 66 No changes 4 4

Untreated F 56 No changes 4 4

Figure 1.

Axial axial PET from PET/CT (A), axial arterial (B) and portal venous (C) phase CT from PET/CT, axial

fused PET/CT (D), coronal PET from PET/MR (E), axial arterial (F) phase contrast enhanced VIBE from

PET/MR, and fused PET/MR (F). A single liver metastasis (arrow) is well appreciated both on the PET

part of PET/CT and on the morphologic and PET images from PET/MR, but not on the CT part of the

PET/CT.

Figure 2.

Coronal CECT (A), fused PET/CT (B), axial PET from PET/CT (C), axial CECT (D), coronal STIR (E),

fused PET/MR (F), axial PET from PET/MR (G), and axial ADC map (H). A left peri-aortic non-regional

lymph node (arrow) does not meet CT size criterion neither demonstrates intense FDG uptake. However

intermediate signal intensity on STIR and restricted diffusion on the ADC map were suggestive of

lymphadenopathy, as confirmed by pathology.

Figure 3.

Axial contrast enhanced CT (A), axial PET from PET/CT (B), axial fused PET/CT (C), axial high

resolution T2 weighted (D), axial PET from PET/MR (E), and fused PET/MR (F). An area of marked FDG

uptake (arrow) is seen in the post-surgical bed in B and D. However, the low soft tissue contrast of CT

(A) is un-capable of resolving the fine details of a post-surgical fistula that are apparent in (D), misleading

the diagnosis toward local recurrence.

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