Multiparametric evaluation by simultaneous PET-MRI examination in patients with histologically proven laryngeal cancer

European Journal of Radiology 88 (2017) 47–55

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Multiparametric evaluation by simultaneous PET-MRI examination in patients with histologically proven laryngeal cancer Carlo Cavaliere a , Valeria Romeo b,∗ , Marco Aiello a , Massimo Mesolella c , Brigida Iorio c , Luigi Barbuto b , Elena Cantone c , Emanuele Nicolai a , Mario Covello a a

IRCCS SDN, Via E. Gianturco, 113-80143, Naples, Italy Department of Advanced Biomedical Sciences, Federico II University, Naples, Italy c Department of Neuroscience, Reproductive and Odontostomatologic Science, ENT Section, Federico II University, Naples, Italy b

a r t i c l e

i n f o

Article history: Received 19 September 2016 Received in revised form 19 December 2016 Accepted 28 December 2016 Keywords: PET/MRI Laryngeal cancer Positron emission tomography Magnetic resonance imaging

a b s t r a c t Objectives: To evaluate the relationship between metabolic 18Fluoro-Deoxyglucose-Positron Emission Tomography (18FDG/PET) and morpho-functional parameters derived by Magnetic Resonance Imaging (MRI) in patients with histologically proven laryngeal cancer. To assess the clinical impact of PET/MRI examination on patient’s staging and treatment planning. Methods: 16 patients with histologically proven laryngeal cancer were enrolled and underwent whole body PET/CT followed by a dedicated PET/MRI of the head/neck region. Data were separately evaluated by two blinded groups: metabolic (SUV and MTV), diffusion (ADC) and perfusion (Ktrans , Ve , kep and iAUC) maps were obtained by positioning regions of interest (ROIs). Tumoral local extension assessed on PET/MRI was compared to endoscopic findings. Results: A good inter-observer agreement was found in anatomical location and local extension of PET/MRI lesions (Cohen’s kappa 0.9). PET/CT SUV measures highly correlate with ones derived by PET/MRI (e.g., p = 0.96 for measures on VOI). Significant correlations among metabolic, diffusion and perfusion parameters have been detected. PET/MRI had a relevant clinical impact, confirming endoscopic findings (6 cases), helping treatment planning (9 cases), and modifying endoscopic primary staging (1 case). Conclusions: PET/MRI is useful for primary staging of laryngeal cancer, allowing simultaneous collection of metabolic and functional data and conditioning the therapeutic strategies. © 2016 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Larynx is involved into about 25% of all head and neck (HN) malignancies [1]. Squamous cell carcinoma (SCC) accounts for more than 90% of these cancers [2]. Tumoral infiltration of deep spaces and laryngeal cartilage is common, with typical patterns depending on the site of origin (i.e. supraglottic, glottic or subglottic) [3]. According to the American Joint Committee on Cancer (AJCC), the TNM classification is universally accepted for laryngeal cancer staging [4]. Information derived by the clinical examination, endoscopy, endoscopic biopsy and cross sectional imaging are integrated for more precise treatment planning and accurate prognostic informations. Magnetic Resonance Imaging (MRI) and Computed Tomography (CT) are considered the primary

∗ Corresponding author at: Department of Advanced Biomedical Sciences, Federico II University, Via S. Pansini 5, 80100, Naples, Italy. E-mail address: [email protected] (V. Romeo). http://dx.doi.org/10.1016/j.ejrad.2016.12.034 0720-048X/© 2016 Elsevier Ireland Ltd. All rights reserved.

imaging modalities for the assessment of HN [5]. On the other hand, 18Fluoro-Deoxyglucose (18F-FDG) PET/CT plays a relevant role for primary staging, especially in the detection of lymph nodes involvement, secondary lesions and syncronous primary cancers [6]. Despite the advantages (sensitivity >95%) and popularity of PET/CT, there are some shortcomings in the use of CT as the complementary anatomical imaging modality, like the poorer soft-tissue contrast compared to MRI [7]; this last limitation can only partially be overcome by contrast-enhanced PET/CT [8]. In particular, due to its greater contrast resolution compared to CT, MRI is extremely useful for anatomical discrimination of head and neck soft tissues [9,10]. MRI is superior to CT also for several specific clinical questions such as laryngeal cartilage invasion, perineural spread, bone marrow invasion, extranodal spread in metastatic neck nodes and vascular and lymphatic invasion [11,12]. Moreover, MRI has the capability to evaluate several functional parameters in vivo, like diffusion parameters predictive of response to treatment [13], and perfusion maps from dynamic contrast enhanced MRI (DCEMRI) [14]. Initial reports on the use of integrated PET/MRI in HN

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SCCs showed better detailed resolution and greater image contrast in comparison to PET/CT and a good correlation between metabolic measures achieved by PET during consecutive PET/CT and PET/MRI scans. [9,10]. [18F]-FDG PET/MRI is highly accurate in the evaluation of primary extension (T-staging) of HNC lesions; on the other hand, PET/MRI gives a lower contribution in detecting lymph nodes involvement (N-staging) and distant metastasis (M-staging) when compared to PET/CT examination [9]. Previous clinical studies have addressed the clinical workflow, the feasibility and optimized imaging protocols for HN imaging [10,15,16]. Aim of this study was to evaluate and to correlate metabolic data acquired by PET with diffusion and perfusion parameters obtained by MRI in laryngeal cancer in primary staging, exploiting simultaneous PET/MRI. Data were also correlated to clinical and histologic findings collected by endoscopy and biopsy/surgery in order to assess the clinical impact of PET/MRI examination on patient’s staging and treatment planning.

2. Materials and methods 2.1. Patient population and imaging protocol According to our institutional review board authorization and Ethical Committee, from January 2013 up to May 2014, 18 consecutive patients (mean age 62 ± 9.8: 16 males, 2 females) with laryngeal cancer histologically proven by biopsy were enrolled. In order to reduce the influence of post-bioptic reactive changes, PET/MR examination was performed at least 30 days after biopsy. Exclusion criteria consisted of >150 mg/dL blood glucose, pregnancy, and standard contraindications for MRI. One patient did not undergo MR examination due to claustrophobia and was excluded from the study. 17 patients underwent a one day single-injection imaging protocol including PET/CT followed by PET/MRI examination. Informed consent was obtained from all the patients. In detail, our exam protocol consisted of the following steps: patients were fasted for at least 6 h before scanning and prior to FDG injection blood glucose level was measured. A dose of 401 ± 35 MBq of [18F]-FDG dose was injected depending on their body weight. After an uptake period 80 ± 16 min, patients underwent PET/CT scan. Following PET/CT, patients underwent head and neck PET/MRI examination.

2.2. PET/CT acquisition PET/CT acquisition was performed on a Gemini TF (Philips Medical Systems, Best, The Netherlands) tomograph designed with a multi-ring LYSO block detectors system and a nominal axial resolution near the center of field of view of 4.8 mm (FWHM) with absolute sensitivity of 6.6 kcps/MBq. According to our routine protocol for oncological studies, PET data was acquired in sinogram mode for 15 min; matrix size was 144 × 144. PET data were reconstructed by means of LORTF- RAMLA algorithm, thus post filtered with a three-dimensional isotropic gaussian of 4 mm at FWHM. CT-based attenuation maps with a low dose CT scan (120 kV, 80 mA) using commonly employed bi-linear scaling [17]. The acquisition time was 3 min per bed position (BP), with 5\6 BPs (each 21 cm) covering the trunk of the patients starting from the pelvis and moved up toward the head. Following whole body acquisition an additional BP was acquired focusing on the head/neck region. The result was a total acquisition time of approximately 18 min per patient for PET/CT. Patient position was supine with the arms brought together above the head for total body acquisition and with arms resting at the sides for head/neck.

2.3. PET/MRI acquisition PET/MRI was performed on the Biograph mMR (Siemens Healthcare, Erlangen, Germany). This system consists of a 3T MRI scanner featuring high-performance gradient systems (45 mT/m) and a slew rate of 200 T/m/s. The PET/MRI system is equipped with Total Imaging Matrix coil technology (Siemens Healthcare), covering the entire body with multiple integrated radiofrequency surface coils. The coils, patient table and cables have been redesigned for PET/MRI in order to minimize their attenuation and, thus, to allow unimpaired PET acquisition with the coils in place. A fully functional PET system, equipped with the avalanche photodiode technology is embedded into the magnetic resonance gantry. The PET scanner has a spatial resolution of 4.1 mm (FWHM) at 1 cm and of 5.0 mm (FWHM) at 10 cm from the transverse FOV and a sensitivity of 11.72 kcps/MBq at the center of the FOV. On average, the PET/MRI scan started about 40 min after the start of PET/CT acquisition. Bed position was established in order to get a full coverage of the head/neck region. After a correct positioning had been ensured, the combined PET/MRI acquisition started. First, a coronal 2-point Dixon 3-dimensional volumetric interpolated breath-hold T1-weighted MRI sequence was acquired and used for the generation of attenuation maps and for anatomic allocation of the PET results, as previously described [18]. The software of the MRI scanner automatically generated 4 different images: T1-weighted in-phase, T1-weighted out-of-phase, water-only, and fat-only. Simultaneously with the start of the Dixon MRI sequence, PET acquisition started ensuring correct temporal and regional correspondence between MRI and PET data. The PET data acquisition occurred during the entire MR acquisition time, taking delayed acquisition times and radioactive decay into account.

2.4. PET data reconstruction PET data obtained on the PET/CT and PET/MRI scanners were processed with comparable reconstruction and correction algorithms. For both modalities, emission data were corrected for randoms, dead time, scatter, and attenuation. A 3-dimensional attenuation- weighted ordered- subsets expectation maximization iterative reconstruction algorithm (AW OSEM 3D) was applied with 3 iterations and 21 subsets, Gaussian smoothing of 4 mm in full width at half maximum, and a zoom of 1. Attenuation maps were obtained from the CT data by bi-linear transformation, as implemented in the post-processing software of the PET/CT scanner, and were used for attenuation correction of the PET/CT data.

2.5. MRI-based attenuation correction Attenuation correction was performed by means of the attenuation maps generated on the basis of the 2-point Dixon MRI sequences obtained for every BP. This approach has recently been demonstrated to provide results comparable to those of conventional attenuation correction by low dose CT [19]. The procedure has been implemented in the post-processing software of the scanner and operates automatically. The Dixon fat- and water-weighted images were used to create an attenuation map with 4 distinct tissue classes: background, lungs, fat, and soft tissue. Attenuation of the PET signal caused by instrumentation such as the patient bed and the fixed MRI coils is automatically integrated into the attenuation maps. The flexible Total Imaging Matrix coils specifically designed for low attenuation were not included in the attenuation maps.

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2.6. MR acquisition The MRI protocol was performed with a dedicated 16 channels head and neck coil, including: Coronal TIRM (repetition time, echo time, inversion time TR/TE/TI = 5000/84/220 ms); Axial FSE T2-weighted, axial (TR/TE = 5000/117 ms); Axial FSE T1-weighted (TR/TE = 590/9.9 ms); Axial diffusion-weighted imaging (DWI), a single-shot echo planar 2d SPAIR (TR/TE = 6900/64 ms) using three b values: 0, 500 and 800 s/mm2. Perfusion (DCE) studies were obtained with intravenous administration of paramagnetic contrast agent (Magnevist, Bayer, Berlin, Germany) 0,2 ml/kg, a flow rate of 3.5 ml/s, after two pre-contrast transaxial T1Vibe with flip angles of 15 and 2 ◦ followed by a t1vibe tra dynamic (TR/TE = 5.37/1.78 ms) with 50 measurements. Additionally, an axial isovolumetric VIBE FAT SAT T1 weighted and axial FFE FAT SAT T1 weighted (TR/TE = 550/8.5 ms) sequences were acquired. All patients were carefully instructed to refrain from vigorous swallowing or breathing during image acquisition, in particular during the acquisition of DWI sequences. The pre-contrast VIBE T1weighted sequence was repeated, if necessary, in order to ensure patient collaboration before contrast agent injection. The total MR acquisition time was about 30–40 min, including time needed to repeat MR sequences affected by motion artifacts, where necessary. 2.7. Data processing and multiparametric analysis PET data obtained together with CT and MRI examination were processed with comparable reconstruction and correction algorithms. For both modalities, emission data were corrected for randoms, dead time, scatter, and attenuation. In PET images, the Standard Uptake Values (SUV) were calculated automatically by the software (Syngo.via, Siemens Medical Systems, Germany) using the body weight method: SUV = [decay corrected tissue activity (kBq/ml)]/[injected 18F- FDG dose per body weight (kBq/g)]. The maximum SUV (SUVmax) and mean SUV (SUVmean) of the tumor tissue were derived automatically by the software using a volume-of-interest (VOI) method of tissue delineation for both the acquisitions. Moreover, based on SUV values, a volumetric characterization of lesion burden was made, as previously suggested [20], considering a metabolic tumor volume (MTV) with a threshold of 40% of the maximum signal intensity (MTV40). Two groups of one senior radiologist experienced in head and neck imaging (8 and 10 years experience) and one nuclear medicine specialist (9 and 7 years experience), blinded to the PET/CT findings, reviewed local tumor staging on PET/MRI in consensus. A comparison between PET/CT and PET/MRI findings has not been performed considering that the first was performed without contrast agent injection and this could underestimate the CT diagnostic accuracy. Primary tumor size, tumoral structural features and infiltration of neighboring structures were assessed using post-contrast VIBE FAT SAT T1 weighted images. Subsequently, the DCE-MR images were transferred for post-processing to a workstation running commercially available software for tissue perfusion estimation (Tissue 4D, Siemens Medical Systems, Germany). After motion correction and registration of the pre- and post-contrast acquisitions, T1 mapping was automatically performed and a freehand region-of-interest (ROI) was plotted around the tumor including the neighboring vessels (carotid arteries, jugular vein). The pharmacokinetic modeling was based on a two compartment model that allows the calculation of the following parameters: transfer constant between vascular, extravascular and extracellular space (EES) (Ktrans ); the volume of EES (Ve ); the constant between EES and blood plasma (kep ); the initial area under the concentration

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curve (iAUC) [21]. Ktrans is the transfer constant from the plasma to the extracellular extravascular space and a parameter related to vessel permeability and tissue blood flow, the leakage space Ve is a marker of cell density, the kep is the transfer constant from the extracellular extravascular space to plasma and iAUC is related to the amount of blood volume in the tissue of interest. Arterial input function (AIF) was related to gadolinium dose injected and was modeled by a bi-exponential function using an intermediate mode provided by the software. For the subsequent tumor ROI analysis, PET/MRI datasets (PET acquisition, axial T1 post-contrast and axial T2 sequences, axial ADC map, and single perfusion maps for Ktrans , Ve , kep and iAUC) were evaluated into a unified measurements framework customized into Syngo.via software platform (Siemens Medical Solutions) allowing a visual comparison of the multiparametric data. Post-contrast T1-weighted as well as T2-weighted images were utilized to assist in the laryngeal tumor outline in major diameter lesion slice, avoiding necrotic areas and large feeding vessels. Free-hand ROI area value, referred as the tumor size in the major diameter lesion slice, was extracted for each patient. For multiparametric comparisons, the ROI outline was following drawn with same position and extent on each map to automatically extract maximum and mean values for each parameter (SUVmax and SUVmean for the PET; ADCmax and ADCmean for the diffusion; Ktrans , Ve , kep , and iAUC, respectively max and mean for perfusion maps). Moreover, standardized ROIs (1 cm2 ) were placed in the paraspinal muscle of each patient in order to obtain SUV, ADC, and DCE-MRI estimates in the normal tissue and prove any significant difference compared with the tumor tissue.

2.8. Statistical analysis Multiparametric consensus data were exported and analyzed using the Sigmaplot v10.0 program with Sigma- Stat integration v3.2 (SPSS, Erkrath, Germany). A p value of less than 0.05 was considered statistically significant. The values are presented as mean ± standard deviation (SD). The Kolmogorov-Smirnov test was used to test for normal distribution. Cohen’s kappa was used to evaluate agreement for primary tumor detection/extension in PET/MRI between two groups of observers. Any differences in the parameters estimations between the normal and tumor tissue were determined by the t-student test. Spearman’s correlation coefficients were calculated to compare imaging findings to clinical and histological evaluation; in particular, the T parameter obtained from endoscopical evaluation was compared with T parameter obtained from PET/MRI and both were compared with pathological TNM (pTNM), which was surgical in resectable tumoral lesions and bioptic in no resectable tumoral lesions. Moreover, a correlation among MRI and CT based SUV values, and among PET/MRI derived metabolic, diffusion and perfusion parameters has been also investigated. A correlation coefficient ␳ of <0.35 was considered to represent low, 0.36–0.67 moderate, 0.68–0.90 high, >0.90 excellent correlation.

2.9. Clinical evaluation and therapeutic strategies Otolaryngologists made a preliminary evaluation of tumor extension on the basis of laryngoscopy and postulated a therapeutic approach. Thereafter, clinicians posed several questions to Radiologists and Nuclear Medicine Specialists about the possible infiltration of neighboring structures in order to correlate the endoscopic findings with PET/MRI findings and to establish the most appropriate treatment.

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3. Results PET/CT and MRI examinations were acquired in all 17 patients. However, in one case the MR images were significantly affected by several motion artifacts and the patient was excluded from the study. 3.1. Inter-observer agreement An excellent agreement between the two observers groups was found in anatomic allocation and extension of lesions by PET/MRI (96%, Cohen’s kappa 0.9). All lesions were identified in both FDGPET and DCE-MR images. 3.2. Multiparametric evaluation of laryngeal lesions The summary statistics for the FDG-metabolism, diffusion and perfusion measurements in the healthy muscle tissue and in the tumors are reported in Table 1. Representative cases of multiparametric laryngeal imaging are shown in Figs. 1 and 2. Cases analyzed (n = 16) included only histologically-proven laryngeal cancers in primary staging. An high correlation has been detected between lesion extension revealed by PET/MRI and endoscopic evaluation (␳ = 0.72, p = 0.03) and histological findings (␳ = 0.81, p = 0.008). Significant positive correlations have been detected for the VOI SUV measures obtained from both PET/CT and PET/MRI (e.g., ␳ = 0.96, p < 0.001 for PET/MRI SUV Mean vs. PET/CT SUV Mean), and between the MTV estimations (PET/CT MTV vs. PET/MRI MTV: ␳ = 0.89, p < 0.001) (Table 2). An high significant correlation (0.68 > ␳ <0.90) has also been demonstrated between the ROI SUV measures obtained outlining major diameter lesion slice, and the VOI values detected through

Table 1 Summary statistics of the FDG metabolism, diffusion and perfusion measurements in the tumoral lesions and in the normal muscle tissue. Parameter

AGE AREA CT SUV Mean CT MTV MR SUV Mean MR MTV SUV Mean 2D ADC Mean K trans Mean Kep Mean iAUC Mean Ve Mean

Lesion

Muscle

Mean

SD

62 1.28 3.43 11.3 4.62 9.66 11.01 1061.12 283.71 60.76 1080.15 383.65

9.8 1.77 1.73 8.21 2.74 7.52 7.46 387.22 102.08 18.34 432.35 107.67

Mean

SD

1 0.65**

0 0.05

0.73**

0.06

0.75** 1487.6** 50.12* 50.39* 164.17* 101.53*

0.05 101.3 9.71 10.3 23.26 16.05

Note: CT = Computed Tomography, MR = Magnetic Resonance SUV = Standardized Uptake Volume, MTV = Metabolic Tumor Volume, ADC = Apparent Diffusion Coefficient, iAUC = initial Area Under the concentration Curve, SD = Standard Deviation. * p 0.05. ** p 0.01.

PET/CT (e.g., Mean values: ␳ = 0.79, p = 0.02) and PET/MRI examination (e.g., Mean values: ␳ = 0.68, p = 0.05) (Table 3). Conversely, a significant negative correlation has been detected for ADC Mean versus Ktrans Mean (␳ = − 0.48, p = 0.04). SUV estimation and all perfusion parameters (Ktrans , Ve , kep and iAUC) in tumors were significantly higher than in normal muscle tissue in both the groups (*p < 0.05; **p < 0.01) (Figs. 1 and 2; Table 1). Conversely, ADC mean value in tumors was significantly lower than in normal paraspinal muscle (Group 1: p < 0.01) (Figs. 1 and 2; Table 1).

Fig. 1. Example of multiparametric analysis. In A, multiparametric imaging evaluation of morphological (T2, and T1 + C), metabolic (PET) and functional (DWI, ADC, Ktrans , Ve , kep , iAUC) in a 68 y.o male with laryngeal cancer characterized by right vocal cord, false vocal cord and ventricle infiltration (Pt 1). The increase of thickness and enhancement of the tumor site in the morphological acquisitions, the increase of FDG-uptake, the reduced diffusivity in ADC with an increase of perfusion parameters were detected. In the upper left, an endoscopic view of the lesion is also provided.

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Fig. 2. Example of multiparametric analysis. Multiparametric imaging evaluation of morphological (T2, and T1 + C), metabolic (PET) and functional (DWI, ADC, Ktrans , Ve , kep , iAUC) in a 57 y.o male with laryngeal cancer characterized by right true vocal cord, false vocal cord, right ventricle, and subglottic infiltration (Pt 7). The increase of thickness and enhancement of the tumor site in the morphological acquisitions, the increase of FDG-uptake, the reduced diffusivity in ADC with an increase of perfusion parameters were detected. In the upper left, an endoscopic view of the lesion is also provided.

3.3. Clinical evaluation and therapeutic strategies Endoscopic findings, the first postulated therapeutic approach on the basis of endoscopic evaluation, clinician’s questions to radiologists and nuclear medicine specialists, relevant PET/MRI findings and the established therapeutic approach with postsurgical staging (pTNM) are summarized in Table 3. In 2 patients with a tumoral lesion of the left true vocal cord with spared motility addressed to endoscopic laser resection, PET/MRI did not reveal infiltration of the anterior commissure and paraglottic space confirming the endoscopic findings without determine any substantial changes on patient’s treatment planning; similarly,

in 4 cases of patients addressed to partial laringectomy, PET/MRI confirmed the tumoral extension assessed by laringoscopy. In 9 cases of patients with endoscopic locally advanced laryngeal cancer, PET/MRI served as a problem solving modality in order to choose the appropriate therapeutic approach; in particular, in 3 cases PET/MRI only revealed a mild infiltration of the paraglottic space suggesting the partial laringectomy as the most appropriate surgical resection; in 3 cases a larger tumoral extension was detected by PET/MRI for subglottic tumoral extension (case 1), aritenoid cartilage involvement (case 2) and paraglottic space and anterior commissure infiltration (case 3); in the remaining 3 cases, PET/MRI detected a tumoral involvement of

Table 2 Summary statistics of PET/CT and PET/MRI metabolic data.

CT-SUV Max p value CT-SUV Mean p value CT-MTV p value MR-SUV Max p value MR-SUV Mean p value MR-MTV p value SUV ROI Max p value

CT-SUV Mean

CT-MTV

MR-SUV Max

MR-SUV Mean

MR-MTV

SUV ROI Max

SUV ROI Mean

0.964 <0.001

−0.107 0.781

0.929 <0.001

0.929 <0.001

−0.286 0.491

0.786 0.0251

0.821 0.0145

−0.143 0.72

0.964 <0.001

0.964 <0.001

−0.393 0.341

0.75 0.0384

0.786 0.0251

−0.321 0.438

−0.321 0.438

0.893 <0.001

−0.107 0.781

0.143 0.72

1 <0.001

−0.571 0.15

0.714 0.05

0.679 0.05

−0.571 0.15

0.714 0.05

0.679 0.055

−0.214 0.602

−0.0357 0.905 0.85 <0.001

In Bold significant p values. Note: CT = Computed Tomography, MR = Magnetic Resonance, SUV = Standardized Uptake Volume, MTV = Metabolic Tumor Volume, ROI = Region Of Interest, Max = Maximum.

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Table 3 Assessment of the therapeutic approach on the basis of endoscopic and imaging findings for each patient. Endoscopic Examination

Histology

First postulated therapeutic approach

Clinician Questions to Radiologists and Nuclear medicine specialists

PET/MR imaging findings

Established therapeutic approach

P TNM

1

Right TVC, FVC, Ventricle. Motility reduced, transglottic

SCC G2/G3

Reconstructive partial laringectomy,/total laringectomy

Subglottic extension? Thyroid/arytenoid cartilage infilitration? Neck vessels infilitration?

Partial laryngectomy

T3 N0 M0

2

Left TVC. Motility spared

SCC G2

Endoscopic laser resection

AC infilitration? Paraglottic space infilitration?

No subglottic extension; No thyroid/arytenoid cartilage infiltration; No neck vessels infilitration Paraglottic fat infilitration No AC infilitration No paraglottic space infilitration

T1 N0 M0

3

Epiglottis, Glossoepiglottic fold, Aryepiglottic fold, Right FVC, TVC, Arytenoid cartilage, PS. Motility absent

SCC G2/G3

Total laryngectomy/not operable

4

Right FVC, TVC, AC. Motility spared

SCC G2

Endoscopic laser resection

Enlarged type V A B D laser cordectomy laser

T2 N0 M0

5

Right TVC, FVC, AC, Arytenoid cartilage. Motility reduced

SCC G2

Partial laringectomy,/total laringectomy

Partial laryngectomy

T3 N0 M0

6

Right FVC, TVC, Aryepiglottic fold. Motility reduced

SCC G2

Partial laringectomy,/total laringectomy

Total laringectomy

T4a N0 M0

7

TVC, FVC, Right ventricle, Subglottic area. Motility reduced

SCC G3

Partial laringectomy,/total laringectomy

Total laringectomy

T4a N1 M0

8

TVC, Right Ventricle, AC. Motility reduced Left TVC, AC, Subglottic Area. Motility reduced

SCC G2

Partial Laryngectomy Partial laryngectomy

Partial laryngectomy Partial laryngectomy

T3 N0 M0

SCC G2/G3

SCC G2

Partial laryngectomy Partial laringectomy,/total laringectomy

Partial laryngectomy Total laringectomy

T3 N0 M0

SCC G3

Controlateral arytenoid cartilage infilitration? Thyroid cartilage infiltration? Hypopharyngeal medial/lateral/posterior wall extension? Paraglottic space infilitration? Anterior spread? Thyroid/arytenoid cartilage infilitration? Controlateral arytenoid cartilage infilitration? Subglottic extension? Thyroid cartilage infiltration? Paraglottic space infilitration? Hypopharyngeal medial/lateral/posterior wall extension? Subglottic spread? PS involvement? Confirmed subglottic spread? cartilage infilitration? Neck vessels infilitration? Hypopharyngeal/lateral/posterior wall extension? Paraglottic space infiltration? Confirmed AC infiltration? Paraglottic space infiltration? Cartilage infiltration? Confirmed AC infiltration? Paraglottic space infiltration? Confirmed AC infiltration? Arytenoid cartilages infiltration? Subglottic spread?

Transmuscular Type III cordectomy Not operable

9

10 11

Right TVC, AC, Subglottic Area. Motility reduced TVC, FVC, Left ventricle. Motility absent

Controlateral arytenoid cartilage infilitration No thyroid cartilage infiltration Hypopharyngeal posterior wall extension No paraglottic space infilitration Anterior spread No Thyroid/arytenoid cartilage infilitration No controlateral arytenoid cartilage infilitration; No subglottic extension No Thyroid cartilage infiltration Paraglottic space infilitration No hypopharyngeal medial/lateral/posterior wall extension Subglottic spread PS involvement Confirmed subglottic spread Thyroid cartilage infilitration No neck vessels infilitration No hypopharyngeal lateral/posterior wall extension Paraglottic space infiltration Confirmed AC infiltration No paraglottic space infiltration Cartilage infiltration Confirmed AC infiltration Paraglottic space infiltration Confirmed AC infiltration Arytenoid cartilages infiltration No subglottic spread

T4b N1 M0

T4a N0 M0

T3 N0 M0

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Pt

Table 3 (Continued) Endoscopic Examination

Histology

First postulated therapeutic approach

Clinician Questions to Radiologists and Nuclear medicine specialists

PET/MR imaging findings

Established therapeutic approach

P TNM

12

Epiglottis, Glossoepiglottic fold, Aryepiglottic fold, Left TVC, FVC. Motility absent

EC G1/G2

Total laryngectomy/not operable

Deep posterior fascia infiltration

Not operable

T4b N1 M0

13

Left TVC, AC. Motitlity reduced

SCC G2

Partial laryngectomy

T3 N0 M0

Epiglottis, Glossoepiglottic fold, Aryepiglottic fold, Left FVC, PS. Motility spared

SCC G2/G3

Total laryngectomy/not operable

No arytenoid/Thyroid cartilage infilitration Limited subglottic extension Paraglottic space infilitration Confirmed AC infilitration Deep posterior fascia infiltration

Partial laryngectomy

14

Not operable

T4b N0 M0

15

TVC, FVC, Left ventricle, AC, PS. Motility absent

SCC G2/G3

Total laryngectomy/not operable

Confirmed PS infiltration Paraglottic space infilitration Hypopharyngeal medial wall extension No sub-glottic spread

Total laringectomy

T4a N0 M0

16

Left TVC. Motility spared

SCC G2

Endoscopic laser resection

PS spread? Arytenoid/Thyroid cartilages infilitration? Subglottic extension? Paraglottic space infilitration? Hypopharyngeal medial/lateral/posterior wall extension? Arytenoid/Thyroid cartilage infilitration? Subglottic extension? Paraglottic space infilitration? Confirmed AC infilitration? PS infiltration? Arytenoid/Thyroid cartilages infilitration? Paraglottic space infilitration? Hypopharyngealmedial/lateral/ posterior wall extension? Confirmed PS infiltration? Paraglottic space infilitration? Hypopharyngeal medial/lateral/posterior wall extension? Sub-glottic spread? Paraglottic space infiltration? AC infiltration? Anterior spread?

No paraglottic space infiltration No AC infiltration No Anterior spread

Endoscopic laser resection

T1 N0 M0

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Pt

Note: Pt = Patient, PET = Positron Emission Tomography, MR = Magnetic Resonance, TVC = True Vocal Cord, FVC = False Vocal Cord, AC = Anterior Commissure, PS = Pyriform Sinus, SCC = Squamo Cellular Carcinoma.

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the posterior hypopharyngeal wall and a deep cervical fascia infiltration: these patients were considered not operable and were addressed to radio-chemotherapy. Finally, in one patient with tumoral involvement of both right false and true vocal cord and anterior commissure infiltration addressed to endoscopic laser resection, PET/MRI demonstrated a contralateral spread suggesting a more extended endoscopic laser resection.

4. Discussion Currently there is no a unique technique able to correctly identify each tumoral feature of laryngeal cancer but CT, MRI and PET provide complementary informations about the infiltration of neighbor structures, the nodal involvement and the secondary spread. However, the great amount of ionizing radiation and the lower contrast resolution especially in head and neck soft tissue put CT at a disadvantage and the recent introduction of whole-body PET/MRI in clinical practice offers new opportunities for integrated functional-anatomic imaging [22]. Previously, we have investigated the feasibility of PET/MRI in a different subset of 44 patients with head and neck malignancies, founding a significant correlation between SUV measures and metabolic parameters obtained both with PET/CT and PET/MRI [23]. To the best of our knowledge, this is the first study conducted on a selected population consisted of only patients with laryngeal cancer. As a result, we obtained a high inter-observer agreement for lesions detection/extension, a high correlation of imaging findings with clinical and histological evaluations, and a good correlation among several metabolic, diffusion and perfusion parameters in the primary tumor. PET/CT and PET/MRI studies were acquired in 17 patients; in 16 patients MR images were obtained without side effects and were suitable for further evaluation while one patient was excluded from the study because MR images were affected by several motion artifacts. This first result strengthens the feasibility of PET/MRI in a so complex region, like head and neck, with many different tissues in a small space, and possible involuntary motion artifacts, like deglutition, that could bias imaging acquisition. The possibility to perform a truly simultaneous acquisition restricts the acquisition time bypassing co-registration problems, especially for DCE perfusion imaging. The higher soft-tissue resolution of MR imaging over CT as well as the multiplanar capabilities of MR imaging make it a powerful diagnostic tool for more accurate assessment of cartilage involvement and early detection of tumor spread into the deep spaces surrounding the larynx, allowing a finer staging of malignancy and suggesting the most appropriate therapeutic approach; in this regard, many authors reported the usefulness of MRI in the assessment of neoplastic invasion of laryngeal cartilage, perineural tumor spread and pre-epiglottic space invasion [11,12,24]. The excellent agreement between the two observers groups recorded in our study for the anatomic allocation and extension of lesions by PET/MRI and the high correlation between imaging findings and endoscopic/histological evaluation also support the potential role of PET/MRI in laryngeal cancer staging. Kubiessa et al. previously found a very good inter rater agreement in tumor detection with no statistically differences in sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) between 18F-FDG PET/MRI and PET/CT in patients with suspected cancer of the head and neck region [25]. As for the correlation analysis, in our study a significant positive relationship was detected for both the SUV and MTV measures extracted from PET/CT and PET/MRI examinations. These results are in accordance to others that have demonstrated a statistically significant strong correlation between SUV measurements on PET/MRI and PET/CT [26], although other groups suggest

an underestimation of PET-MRI values as compared with PET/CT [15,27]. This effect could be partially due to MRI- based attenuation correction methods. However, the 2-point Dixon approach we used for attenuation correction has recently shown comparable results to conventional CT attenuation correction systems [19]. Regarding diffusion (ADC) and perfusion parameters (Ktrans , Ve , kep , iAUC), in this study we found a significant negative correlation between ADC Mean and Ktrans Mean in cancer lesions with reduced diffusivity and high perfusion in malignant lesions, expression of high cell density and increased permeability due to neoangiogenesis, as also reported by previous authors [28]. Moreover, our finding of a significantly higher SUV and perfusion values (Ktrans , Ve , kep , iAUC) in tumors compared to normal muscle tissue may indicate a possible interaction between vascular environment and tumor metabolism, as previously suggested [29]. Finally, in our study PET/MRI had a relevant clinical impact on patient’s management; it correctly guided clinicians as a problem solving modality identifying a larger tumoral extension in 10 patients, suggesting a different surgical approach, and contraindicated surgery in 3 patients. Our study has several limitations. First, according to our institutional review board, PET/CT had to be acquired before PET/MRI; so that, PET/MRI was performed about 100 min after FDG injection, even if many authors reported that delayed PET acquisition could improve image quality [30]. Second, our patients had not concordant use of contrast agent, since we performed un-enhanced PET/CT and enhanced PET/MRI. Considering this different use of contrast agent, it was not possible to perform a comparison between PET/CT and PET/MRI findings. 5. Conclusions In conclusion, PET/MRI is useful for the staging of laryngeal cancer since it provides metabolic data comparable to that of PET/CT and determines a significant impact on patient’s treatment planning. Advantages of this tool are represented by the possibility to simultaneously collect metabolic (SUV and MTV), anatomical (tumor size and extension over neighbor structures) and functional parameters (ADC, Ktrans , Ve , kep , iAUC) that better characterize tumoral features. Further improvements are needed for the development of surface dedicated coils, dual modality contrast agents, and finer quantitative strategies in order to maximize the benefits and usefulness of hybrid PET/MRI. Conflict of interest All authors state that there are no conflicts of interest to declare References [1] D.M. Parkin, F. Bray, J. Ferlay, P. Pisani, Global cancer statistics 2002, CA. Cancer J. Clin. 55 (2) (2005) 74–108. [2] B.A. Shiff, Merck Manuals, tumors of the head and neck, Overview of Head and Neck Tumors. http://merckmanuals.com (2016) (accessed 15.05.16). [3] M. Becker, Larynx and hypopharynx, Radiol. Clin. North Am. 36 (5) (1998) 891–920. [4] The american Joint committee on cancer: AJCC staging manual, in: F.L. Greene (Ed.), American Joint Committee on Cancer: Larynx, 7th ed., Springer, NY, 2010, pp. 57–68. [5] H. Kuno, H. Onaya, S. Fujii, H. Ojiri, K. Otani, M. Satake, Primary staging of laryngeal and hypopharyngeal cancer: CT, MR imaging and dual-energy CT, Eur. J. Radiol. 83 (1) (2014) e23–25. [6] A. Quon, N.J. Fischbein, I.R. McDougall, et al., Clinical role of 18F-FDG PET/CT in the management of squamous cell carcinoma of the head and neck and thyroid carcinoma, J. Nucl. Med. 48 (1) (2007) 58S–67S. [7] R. Hermans, F. De Keyzer, V. Vandecaveye, Imaging technique, in: A.L. Baert, K. Sartor (Eds.), Head and Neck Cancer Imaging, Springer Berlin Heidelberg, New York, 2006, p. p.32. [8] D. Mak, J. Corry, E. Lau, D. Rischin, R.J. hicks, Role of FDG-PET/CT in staging and follow-up of head and neck squamous cell carcinoma, Q. J. Nucl. Med. Mol. Imaging 55 (5) (2011) 487–499.

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