cancers

Article Prediction of Posterior Paraglottic Space and Cricoarytenoid Unit Involvement in Endoscopically T3 Glottic Cancer with Arytenoid Fixation by Magnetic Resonance with Surface Coils

Marco Ravanelli 1 , Alberto Paderno 2,*, Francesca Del Bon 2, Nausica Montalto 2, Carlotta Pessina 1, Simonetta Battocchio 3, Davide Farina 1, Piero Nicolai 2, Roberto Maroldi 1 and Cesare Piazza 4

1 Department of Radiology, University of Brescia, 25123 Brescia, Italy; [email protected] (M.R.); [email protected] (C.P.); [email protected] (D.F.); [email protected] (R.M.) 2 Department of Otorhinolaryngology—Head and Surgery, University of Brescia, 25123 Brescia, Italy; [email protected] (F.D.B.); [email protected] (N.M.); [email protected] (P.N.) 3 Department of Pathology, University of Brescia, 25123 Brescia, Italy; [email protected] 4 Department of Otorhinolaryngology, Maxillofacial, and Surgery, Fondazione IRCCS, Istituto Nazionale dei Tumori di Milano, University of Milan, 20133 Milan, Italy; [email protected] * Correspondence: [email protected]

 Received: 7 December 2018; Accepted: 4 January 2019; Published: 10 January 2019 

Abstract: Discrimination of the etiology of arytenoid fixation in cT3 laryngeal squamous cell carcinoma (SCC) is crucial for treatment planning. The aim of this retrospective study was to differentiate among possible causes of arytenoid fixation (edema, inflammation, mass effect, or tumor invasion) by analyzing related signal patterns of magnetic resonance (MR) in the posterior laryngeal compartment (PLC) and crico-arytenoid unit (CAU). Seventeen patients affected by cT3 glottic SCC with arytenoid fixation were preoperatively studied by state-of-the-art MR with surface coils. Different signal patterns were assessed in PLC subsites. Three MR signal patterns were identified: A, normal; B, T2 hyperintensity and absence of restriction on diffusion-weighted imaging (DWI); and C, intermediate T2 signal and restriction on DWI. Signal patterns were correlated with the presence or absence of CAU and PLC neoplastic invasion. Patients were submitted to open partial horizontal or total laryngectomy and surgical specimens were analyzed. Pattern A and B did not correlate with neoplastic invasion, while Pattern C strongly did (Spearman’s coefficient = 0.779, p < 0.0001; sensitivity: 100%; specificity: 78%). In conclusion, MR with surface coils is able to assess PLC/CAU involvement with satisfactory accuracy. In absence of Pattern C, arytenoid fixation is likely related to mass effect and/or inflammatory reaction and is not associated with neoplastic invasion.

Keywords: ; magnetic resonance imaging; surface coils; posterior laryngeal compartment; cricoarytenoid unit

1. Introduction Endoscopic evaluation represents a paramount diagnostic and staging tool for the assessment of laryngeal tumors. Vocal fold (i.e., arytenoid) fixation in glottic squamous cell carcinoma (SCC) leads to classification in the cT3 category according to the 7th Edition of the AJCC UICC TNM staging system (unchanged in the subsequent 8th Edition) [1,2]. This clinical sign has recently been better defined by Rosen et al. [3] as “vocal fold immobility related to laryngeal malignant disease”. However, such a clinical diagnosis may either underestimate the true neoplastic extent (e.g., pT4 with clinically

Cancers 2019, 11, 67; doi:10.3390/cancers11010067 www.mdpi.com/journal/cancers Cancers 20192019,, 1111,, 67x 2 of 1112

with clinically silent cartilage invasion or extralaryngeal spread) or overestimate it (e.g. in “simple” silentpT2 when cartilage the invasioncricoarytenoid or extralaryngeal unit (CAU) spread)is only orimpaired overestimate in its itnormal (e.g., in function “simple” by pT2 peritumoral when the cricoarytenoidedema or tumor unit bulk (CAU) rather is only than impaired by true in itsneopla normalstic function infiltration). by peritumoral On the other edema hand, or tumor from bulk an ratheretiopathological than by true point neoplastic of view, infiltration). vocal fold/aryteno On the otherid immobility hand, from ancan etiopathological be related to pointa number of view, of vocaldifferent fold/arytenoid factors: invasion immobility of the can CAU, be related intrinsic to alaryngeal number ofmuscle different involvement, factors: invasion infiltration of the of CAU, the intrinsicintra- and/or laryngeal extralaryngeal muscle involvement, supply, infiltration volume of (mass) the intra- effect, and/or and inflammatory extralaryngeal changes. nerve supply, This volumeleads to (mass) substantial effect, anddiagnostic inflammatory uncertainty, changes. sinc Thise these leads conditions to substantial have diagnostic relevant uncertainty, and dissimilar since theseclinical conditions implications. have relevantFor example, and dissimilar in a recently clinical implications.published multicentric For example, study in a recently on T3 published and T4 multicentriclaryngeal SCC study treated on T3 by and open T4 laryngealpartial horizont SCC treatedal laryngectomies by open partial (OPHLs), horizontal pT3 laryngectomies tumors with (OPHLs),posterior laryngeal pT3 tumors compartment with posterior (PLC) laryngeal invasion compartment (i.e. the paraglottic (PLC) invasion space located (i.e., the posterior paraglottic to spacea line locateddrawn from posterior the arytenoid to a line vocal drawn process from the perpendicu arytenoidlarly vocal to the process thyroid perpendicularly cartilage, of which to the the thyroid CAU cartilage,represents of a whichkey structure) the CAU demonstrated represents a key signific structure)antly worse demonstrated prognosis significantly than anteriorly worse located prognosis pT4 thanlesions anteriorly [4]. For locatedthis reason, pT4 lesionsthe theoretical [4]. For thisplane reason, dividing the theoreticalthe anterior plane from dividing the PLC the was anterior also called from theby the PLC authors was also the called “magic by plane” the authors (Figure the 1). “magic plane” (Figure1).

Figure 1.1.Anatomical Anatomical section section representing representing the the glottic glottic plane plane on a transverseon a transverse section: section: dashed linedashed (“magic line plane”(“magic according plane” according to Succo etto al. Succo [4]) indicateset al. [4] the) indicates limit dividing the limit the dividing anterior (green)the anterior from (green) the posterior from (red)the posterior laryngeal (red) compartments. laryngeal comp Legend:artments. Ac, arytenoid Legend: cartilage; Ac, arytenoid tc, ; cartilage; tc, vm,thyroid vocal cartilage; muscle. vm, vocal muscle. Imaging has the ability to accurately delineate submucosal tumor extension in order to elucidate the causeImaging of arytenoid has the hypomotilityability to accurately or fixation. delineate In particular, submucosal we have definedtumor extension as “arytenoid in order fixation” to theelucidate complete the immobilitycause of arytenoid of both thehypomotility vocal fold andor fixation. arytenoid In cartilage particular, [3]. we Magnetic have defined resonance as (MR)“arytenoid offers fixation” higher contrast the complete resolution immobility than computed of both tomography the vocal fold (CT) and and arytenoid is particularly cartilage helpful [3]. inMagnetic distinguishing resonance tumor (MR) infiltrationoffers higher from contrast peritumoral resolution inflammation, than computed and tomography in depicting (CT) cartilage and is infiltrationparticularly [5helpful]. State in of distinguishing the art protocols, tumor including infiltration use offrom surface peritumoral coils, enhance inflammation, the potential and ofin thedepicting technique cartilage by significantly infiltration increasing [5]. State of its the spatial art protocols, resolution. including use of surface coils, enhance the potentialThe aim of of the this technique study was by tosignificantly explore the increasing capability its of spatial MR in resolution. assessing the PLC, with special emphasisThe aim given of this to evaluationstudy was ofto CAU,explore in the clinically-defined capability of MR T3 in SCCassessing with the arytenoid PLC, with fixation special at preoperativeemphasis given endoscopic to evaluation evaluation. of CAU, in clinically-defined T3 SCC with arytenoid fixation at preoperative endoscopic evaluation. 2. Materials and Methods 2. Materials and Methods 2.1. Patient Selection 2.1. PatientThe present Selection retrospective study was performed in a tertiary academic center. It included 17 patients (13 males and four females: mean age, 65 years; age range, 48–82) with histologically The present retrospective study was performed in a tertiary academic center. It included 17 patients (13 males and four females: mean age, 65 years; age range, 48–82) with histologically Cancers 2019, 11, 67 3 of 11

Cancers 2019, 11, x 3 of 12 demonstrated glottic SCC defined as cT3 for arytenoid fixation via transnasal flexible videoendoscopy. demonstrated glottic SCC defined as cT3 for arytenoid fixation via transnasal flexible This is a purely retrospective study with no need to receive approval from ethics committee, and no videoendoscopy. This is a purely retrospective study with no need to receive approval from ethics informed consent was signed. Each examination was video-recorded and separately re-evaluated committee, and no informed consent was signed. Each examination was video-recorded and byseparately two experienced re-evaluated laryngologists/head by two experienced and necklaryngologists/head surgeons to confirm and neck the surgeons clinical immobility to confirm ofthe the vocalclinical fold withimmobility arytenoid of the fixation. vocal MRfold was with performed arytenoid in fixation. the same MR institution was performed within two in weeksthe same from surgery.institution All patientswithin two were weeks subsequently from surgery. treated All pati byents OPHL were or subsequently total laryngectomy treated by (TL) OPHL according or total to clinicallaryngectomy staging, patient(TL) according comorbidities, to clinical and staging, preference. patient A comorbidities, flow-chart of and patient preference. selection A flow-chart is shown in Figureof patient2. selection is shown in Figure 2.

FigureFigure 2. 2.Selection Selection schema: schema: flowflow chartchart ofof patientpatient enrollmentenrollment in in the the present present study. study. Legend: Legend: MR, MR, magneticmagnetic resonance; resonance; SCC, SCC, squamoussquamous cellcell carcinoma;carcinoma; TLM, TLM, transoral transoral laser laser microsurgery; microsurgery; (C)RT, (C)RT, (chemo)radiotherapy.(chemo)radiotherapy. 2.2. MR Study Protocol 2.2. MR Study Protocol MRMR studies studies were were performed performed onon aa 1.5T1.5T SiemensSiemens Avanto or Siemens Siemens Aera Aera scanner scanner (Siemens (Siemens Healthcare,Healthcare, Erlanghen, Erlanghen, Germany) Germany) using using twotwo smallsmall loop coils (circular (circular coils coils with with a adiameter diameter of of4 cm 4 cm specificallyspecifically designed designed to to provide provide improved improved signal-to-noisesignal-to-noise ratios by by limiting limiting the the spatial spatial extent extent of ofthe the excitationexcitation and and reception) reception) directly directly appliedapplied toto thethe larynxlarynx as as per per standard standard prot protocolocol in in our our institution. institution. TheThe MR MR protocol protocol included included high high resolution resolution TSE-T2TSE-T2 andand TSE-T1 sequences sequences (with (with slice slice thicknesses thicknesses rangingranging from from 2 to2 to 3 mm3 mm and and a a matrix matrix ofof 512512 oror 448448 withwith reduced field field of of view) view) which which were were often often replacedreplaced in in uncooperative uncooperative patients patients by by sequences sequences withwith motion-compensation (radial (radial k-space k-space filling) filling) withwith a 320 a 320 matrix. matrix. Diffusion-weighted Diffusion-weighted imaging imaging (DWI) (DWI) was was acquired acquired with with monopolar monopolar gradients gradients and and two b-valuestwo b-values (0 and 1000(0 and mm/s 10002). mm/s After2). contrast After contrast injection, injection, a 3D GE a sequence 3D GE sequence with fat saturationwith fat saturation (VIBE) was acquired(VIBE) withwas 0.6acquired mm voxel with size; 0.6 inmm uncompliant voxel size; patients, in uncompliant it was replaced patients, with it was a motion-compensated replaced with a sequencemotion-compensated with 0.7 mm voxelsequence size with sequence 0.7 mm (StarVIBE). voxel size sequence (StarVIBE). CancersCancers2019 2019, 11, ,11 67, x 4 of4 12 of 11

2.3. Image Analysis 2.3. Image Analysis Images were reviewed in consensus by two experienced head and neck radiologists blinded on theImages videoendoscopic were reviewed examination, in consensus type by of two surg experiencedery performed, head and intraope neck radiologistsrative findings, blinded and on thedefinitive videoendoscopic histopathologic examination, report. typeThe PLC of surgery was defi performed,ned as the intraoperativearea located behind findings, a line and drawn definitive in histopathologicthe axial plane report. from Thethe vocal PLC wasprocess defined of the as ar theytenoid area located to the behindipsilateral a linethyroid drawn lamina in the and axial planeperpendicular from the vocalto the process latter of(Figure the arytenoid 1). In this to the compartment, ipsilateral thyroid the following lamina andstructures perpendicular were tosystematically the latter (Figure assessed:1). In thisthe compartment,posterior portion the of following the vocal structures (medial thyro-arytenoid) were systematically muscle, assessed: the thelateral posterior crico-arytenoid portion of theand vocal crico-thyroid (medial thyro-arytenoid)muscles, the posterior muscle, portion thelateral of the crico-arytenoidparaglottic space and crico-thyroid(PGS) (i.e. the muscles, part of thethe PGS posterior located portion into the of PLC the paraglotticas defined above), space (PGS)the inferior (i.e., thePGS part (i.e.of the the part PGS locatedof the intoPGS thelocated PLC below as defined the vocal above), , the inferior lateral to PGS the (i.e., conus the elasticus, part of theand PGSmedial located to the below cricoid the vocalcartilage), ligament, the lateralarytenoid, to the and conus the cricoid elasticus, cartilage. and medial To assess to the cartilage cricoid invasion cartilage), we theused arytenoid, the criteria and proposed by Becker et al. [6]. Each of these structures was categorized according to their signal the . To assess cartilage invasion we used the criteria proposed by Becker et al. [6]. pattern in the different sequences: Each of these structures was categorized according to their signal pattern in the different sequences: Pattern A: normal signal intensity in all sequences; Pattern A: normal signal intensity in all sequences; Pattern B: tissue changes characterized by T2 hyperintensity, no DWI restriction (high Patternapparent B: tissuediffusion changes coefficient characterized (ADC)), and by T2variable hyperintensity, contrast-enhancement. no DWI restriction For ossified (high apparentcartilages: diffusion T2 hyperintensity coefficient, T1 (ADC)), hypointensity, and variable and brig contrast-enhancement.ht contrast enhancement; For ossified cartilages: T2 hyperintensity, T1 hypointensity, and bright contrast enhancement; Pattern C: tissue abnormalities characterized by T2 intermediate signal, DWI restriction Pattern(high C:DWI tissue signal abnormalities combined characterizedwith low ADC by value), T2 intermediate and variable signal, contrast-enhancement. DWI restriction (high DWIFor signal ossified combined cartilages: with T2 lowintermediate ADC value), signal, and T1 variable hypointensity, contrast-enhancement. and intermediate For contrast ossified cartilages:enhancement. T2 intermediate signal, T1 hypointensity, and intermediate contrast enhancement.

PatternPattern B B was was considered considered consistent consistent withwith high water content content within within tissues tissues and and was was thus thus more more likely to be associated with inflammatory changes (Figures 3 and 4), while Pattern C was likely to be associated with inflammatory changes (Figures3 and4), while Pattern C was considered considered more likely to be consistent with tumor infiltration (Figure 5). more likely to be consistent with tumor infiltration (Figure5). Scores (0 for Pattern A, 1 for Pattern B, and 2 for Pattern C) for each subsite (n = 7) were Scores (0 for Pattern A, 1 for Pattern B, and 2 for Pattern C) for each subsite (n = 7) were summed summed to obtain three different scores. The “Overall Score” (ranging from 0 to 14) was derived to obtain three different scores. The “Overall Score” (ranging from 0 to 14) was derived from the sum from the sum of the scores assigned to each subsite. The “Partial Score Pattern B” (ranging from 0 to of the7) was scores derived assigned from to the each sum subsite. of each The subsite “Partial receiving Score Patterna score B”of 1. (ranging The “Partial from 0Score to 7) Pattern was derived C” from(ranging the sum from of each0 to subsite14) wasreceiving derived from a score the of sum 1. The of each “Partial subsite Score receiving Pattern C”a score (ranging of 2. fromThe three 0 to 14) wasscores derived were from then the correlated sum of each with subsite specific receiving histopathological a score of findings 2. The three as described scores were in the then statistical correlated withanalysis specific section. histopathological findings as described in the statistical analysis section.

Figure 3. Cont. Cancers 2019, 11, x 5 of 12 Cancers 2019, 11, 67 5 of 11 Cancers 2019, 11, x 5 of 12

Figure 3. Example of Pattern B. From top to the bottom: (a) TSE-T2 on coronal plane; (b) TSE-T2 on axialFigureFigure plane. 3. 3.Example ExampleA right ofglottic of Pattern Pattern tumor B. B. From Fromthat doestop top toto not thethe in bottom:bottom:vade the ( (aa posterior)) TSE-T2 TSE-T2 on laryng on coronal coronaleal compartmentplane; plane; (b ()b TSE-T2) TSE-T2 (PLC) on on is seen.axialaxial plane.In plane. (a), Anormal A right right glottic signalsglottic tumor tumor of lateral that that does doescricoarytenoid notnot invadeinvade the and posteriorposterior cricothyroid laryng laryngeal muscleseal compartment compartment are displayed, (PLC) (PLC) isthe is cricoidseen.seen. In lamina (Ina), (a normal), isnormal normal, signals signals and of lateral anof lateralinferior cricoarytenoid cricoarytenoid paraglottic and space and cricothyroid cricothyroid(PGS) is musclesindicated muscles are by displayed,are dotted displayed, lines. the cricoid Inthe (b ), expansionlaminacricoid is normal,lamina of the isright and normal, anPLC inferior and(dotted an paraglottic inferior black lines) paraglottic space is seen (PGS) space. A is high indicated(PGS) T2 issignal indicated by dotted in th eby lines.PLC dotted is In consistent (lines.b), expansion In ( bwith), anof theexpansionintense right edema PLC of the (dotted rightthat PLChampers black (dotted lines) crico-arytenoid black is seen. lines) A high is seenun T2it. signalA(CAU) high inT2 functionality. the signal PLC in is th consistente PLCLegend: is consistent with Ac, anarytenoid intensewith cartilages;edemaan intense that CL, hampers edema cricoid that crico-arytenoid lamina; hampers ctm, crico-arytenoid unitcricothyroid (CAU) functionality.un muscle;it (CAU) e, functionality. Legend:edema; lcam, Ac, arytenoidLegend: lateral Ac, cricoarytenoid cartilages; arytenoid CL, muscle.cricoidcartilages; lamina; CL, ctm, cricoid cricothyroid lamina; muscle;ctm, cricothyroid e, edema; lcam,muscle; lateral e, edema; cricoarytenoid lcam, lateral muscle. .

FigureFigure 4. 4. 4.Example ExampleExample of of Pattern ofPattern Pattern B, B, indicating indicating B, indicating fusionfusion fusionbetween between aa T2-weightedT2-weighted a T2-weighted sequence sequence and sequenceand a diffusion-a diffusion- and a weighteddiffusion-weightedweighted imaging imaging (DWI) imaging(DWI) image. image. (DWI) “Hot” “Hot” image. areasareas “Hot” corresponcorrespon areasd toto correspond thethe anterioranterior toglottic glottic the anteriortumor. tumor. A glottic Adotted dotted tumor.line line Aseparates dottedseparates linethe the separatestumor tumor from from the tumorthe the peritumoralperitumoral from the peritumoral edema.edema. The edema. laterallateral The cricoarytenoidcricoarytenoid lateral cricoarytenoid muscle muscle is isnormal. muscle normal. is Legend:normal.Legend: Legend:e, e,edema; edema; e, lcam, edema; lcam, lateral lateral lcam, cricoarytenoid cricoarytenoid lateral cricoarytenoid muscle; T, muscle; tumor.tumor. T, tumor.

Imaging findings were compared to definitive histopathological evaluations of formalin-fixed surgical specimens after OPHL or TL: in 11 patients, the report overtly described the PLC as invaded or not. In six patients, revision of macrosections was required and performed by a dedicated pathologist since such information was missing in the original report or was not clear enough. In these cases, the criterion used to identify or rule out the PLC invasion was the presence of neoplastic cell nests posterior to the aforementioned “magic plane” (Figure1). Cancers 2019, 11, 67 6 of 11 Cancers 2019, 11, x 6 of 12

FigureFigure 5. Example 5. Example of Pattern of Pattern C. From C. From top top to bottom:to bottom: (a )(a TSE-T2) TSE-T2 on on coronal coronal plane;plane; (b)) TSE-T2 on on axial plane.axial In (a )plane. the right In (a glottic-subglottic) the right glottic-subglottic tumor infiltrates tumor inf theiltrates inferior the inferior PGS (curved PGS (curved arrow) arrow) extending extending outside the , the vocal and lateral cricoarytenoid muscles are partially infiltrated, outside the larynx, the vocal and lateral cricoarytenoid muscles are partially infiltrated, and the and the cricoarytenoid muscle is completely undetectable because of invasion (the same muscles are cricoarytenoid muscle is completely undetectable because of invasion (the same muscles are normally normally visible on the left side). There is infiltration of the right cricoid lamina, although it is visiblenormal on the on left the side). left Thereside. In is ( infiltrationb) the tumor of infiltrates the right the cricoid lateral lamina, cricoarytenoid although and it cricothyroid is normal on the left side.muscles, In (b) visible the tumor on the infiltrates left side. the Arrowheads lateral cricoarytenoid indicate the andright cricothyroid thyroid lamina, muscles, which visible is not on the left side.infiltrated. Arrowheads A curved indicate dotted theline rightand arrow thyroid indicate lamina, the posterior which is front not of infiltrated. the neoplasm. A curved Legend: dotted CL, line and arrowcricoid indicate lamina; the ctm, posterior cricothyroid front muscle; of the lcam, neoplasm. lateral Legend:cricoarytenoid CL, cricoidmuscle; lamina;T, tumor; ctm, vm, cricothyroid vocal muscle;muscle. lcam, lateral cricoarytenoid muscle; T, tumor; vm, vocal muscle.

2.4. StatisticalImaging Analysis findings were compared to definitive histopathological evaluations of formalin-fixed surgical specimens after OPHL or TL: in 11 patients, the report overtly described the PLC as Spearman’sinvaded or testnot. was In usedsix patients, to assess revision correlation of macrosections between CAU was infiltration required and and performed different MR by patterns.a Area Underdedicated the Receiverpathologist Operating since such Curve information (AUROC) was missing was used in the to assessoriginal if thereport three or was radiological not clear scores had anenough. association In these with cases, histology the criterion and diagnosticused to identi performancefy or rule out usingthe PLC the invasion best cut-off was the value. presence Statistical significanceof neoplastic was fixed cell nests at 0.05. posterior All statistical to the aforementioned tests were performed “magic plane” in MedCalc (Figure 1). (MedCalc Software bvba, Ostend, Belgium). 2.4. Statistical Analysis 3. Results Spearman’s test was used to assess correlation between CAU infiltration and different MR patterns. Area Under the Receiver Operating Curve (AUROC) was used to assess if the three Patientsradiological and CAU/PLC scores Infiltration had an association with histology and diagnostic performance using the best cut-off value. Statistical significance was fixed at 0.05. All statistical tests were performed in FigureMedCalc2 gives (MedCalc a flow Software chart of bvba, patient Ostend, enrollment. Belgium). Table1 summarizes the baseline characteristics of patients and the type of surgery they received, while Table2 shows the three scores calculated for each patient. Upon definitive histopathological examination, eight (47%) patients showed involvement of the PLC. With MR, one (6%) patient of the 17 had Score 0 (related to Pattern A) in all subsites and sequences: histology confirmed no signs of PLC involvement (true negative). Six (35%) had Score 1 (Pattern B) in at least one subsite, without any Score 2 (Pattern C): histology showed no signs of PLC Cancers 2019, 11, 67 7 of 11 infiltration (true negatives). Ten (59%) patients had Score 2 (Pattern C) in at least one subsite: histology showed PLC invasion in eight cases (true positives). Two patients turned out to have false positives. In Table2, the three MR scores per each patient are reported and compared to their histology. Spearman’s test demonstrated no correlation between the “Partial Score Pattern B” and neoplastic involvement of PLC (−0.0124; CI 95%, −0.490–0.471; p = 0.9624), while the “Overall Score” showed significant positive correlation with PLC infiltration (0.690; CI 95%, 0.313–0.879; p = 0.002). However, the strongest correlation was found between PLC infiltration and “Partial Score Pattern C” (0.779; CI 95%, 0.477–0.916; p = 0.0002). Using “Partial Score Pattern C” as a dependent variable and histopathological status as the reference, an AUROC curve of 0.931 (CI 95%, 0.698–0.997) was obtained (Figure6), using 2 as the best cut-off (100% sensitivity and 78% specificity). This means that if at least one of the considered structures in the PLC is characterized by Pattern C (Score 2), a neoplastic origin of arytenoid fixation is suggested (to be confirmed upon histopathological examination). On the other hand, if these changes are absent, neoplastic involvement is very unlikely. Cancers 2019, 11, x 8 of 12 Table 1. Baseline patient, tumor, and surgical procedure characteristics. Legend: OPHL, open partial horizontalTable laryngectomy; 1. Baseline patient, TL, tumor, total laryngectomy; and surgical procedure ND, neck characteristics. dissection. Legend: OPHL, open partial horizontal laryngectomy; TL, total laryngectomy; ND, neck dissection. Mean Age 64.9 years (range)Mean age 64.9(45–82) years years Gender(range) (45–82)13 years M, 4 F Gender 13 M, 4 F cT 17 cT3 cT 17 cT3 11 cN0 cN 11 cN0 cN 6 cN+ 6 cN+ 13 pT3 pT 13 pT3 pT 4 pT4a 4 pT4a 8 pN08 pN0 2 pN2a pN 2 pN2a pN 5 pN2b 5 pN2b 2 pN2c 2 pN2c 10 OPHL Surgery 10 OPHL Surgery 7 TL 7 TL 10 bilateral10 bilatera ND ND 7 unilaterall7 unilateral

FigureFigure 6. Area 6. Area under under the the curve curve ofof PartialPartial Score Pattern Pattern C. C.The The optimal optimal cut-off cut-off value valuewas 2,was 2, correspondingcorresponding to one to subsiteone subsite with with Pattern Pattern C C signal signal abnormalities. Cancers 2019, 11, 67 8 of 11

Table 2. Magnetic resonance (MR) signal changes in PLC subsites. Legend: POST, posterior; VM, vocal (thyro-arytenoid) muscle; PGS, paraglottic space; ARY, ; CRIC LAM, cricoid lamina; LCAM, lateral crico-; CTM, crico-thyroid muscle; CAU, crico-arytenoid unit; PLC, posterior laryngeal compartment.

Overall Partial Score Partial Score Histological ID POST VM POST PGS INF PGS ARY CRIC LAM LCAM CTM Score of Pattern B of Pattern C CAU/PLC Infiltration 1 1 0 0 0 0 0 0 1 1 0 0 2 1 1 1 0 0 1 0 4 4 0 0 3 2 2 0 0 0 0 0 4 0 4 0 4 0 1 1 0 0 1 0 3 3 0 0 5 1 1 0 0 0 1 0 3 3 0 0 6 2 0 2 0 2 2 2 10 0 10 1 7 0 1 1 0 0 1 0 3 3 0 0 8 2 1 1 0 0 2 0 6 2 4 1 9 2 2 2 1 0 2 0 9 1 8 1 10 2 2 2 1 0 2 1 10 2 8 1 11 2 1 1 1 0 1 1 7 5 2 1 12 2 1 0 0 0 0 0 3 1 2 0 13 1 0 0 0 0 0 0 1 1 0 0 14 0 0 0 0 0 0 0 0 0 0 0 15 2 0 0 0 0 1 0 3 1 2 1 16 2 2 1 2 0 1 0 8 2 6 1 17 2 1 0 0 0 0 0 3 1 2 1 Cancers 2019, 11, 67 9 of 11

4. Discussion CT is widely used as a first-choice technique in the staging and treatment planning of laryngeal SCC. However, with this technique the assessment of the PLC has some intrinsic limitations. Even after contrast administration, in fact, the density of the tumor overlaps with that of adjacent soft tissues, making discrimination between normal and invaded structures difficult. This is explained by the fact that adipose tissue, which in other subsites of the larynx (like the pre-epiglottic space and upper PGS) facilitates the definition of the deep extent of the tumor, is usually under-represented in the PLC at the glottic level [7,8]. In addition, although spatial resolution of CT allows detection of subtle anomalies of the cortical bone of ossified cartilages, bone marrow alterations are difficult to spot and the diagnostic value of ancillary findings, like arytenoid sclerosis, is limited [9]. This may be improved by dual-energy CT, but the sensitivity remains low compared to MR [10,11]. In our study, we evaluated a small but extremely homogeneous retrospective cohort of patients affected by cT3 glottic SCC with arytenoid fixation as indicated by preoperative videolaryngoscopy. Due to the key role of clinical staging, preoperative video-recordings were further reviewed upon inclusion in the study to confirm the presence of true CAU fixation (cT3). Our results showed that accurate MR analysis may predict tumor infiltration of CAU and, more generally, of PLC, distinguishing it from inflammatory changes. In fact, if a state-of-the-art technique (including surface coils, adequate spatial resolution, and special sequences for uncooperative patients) is used, the morphologic and signal changes of all structures can be appropriately identified. Interestingly, Pattern B was never associated with neoplastic infiltration. Notably, although the combination of a high-T2 signal and the absence of DWI restriction is an accepted pattern of inflammation, in our study the detection of these signal changes actually corresponded to the complete absence of neoplastic cells even on a microscopic scale, and not to a mix of abundant inflammatory infiltrate and sparse neoplastic cells. Furthermore, Pattern C was mainly associated with tumor infiltration (with the exception of two false positives in the present series), as described in the literature in recurrences after transoral laser microsurgery [12]. To the best of our knowledge, no study has focused on a similar topic with which we could compare our results. In view of its excellent negative predictive value, MR may represent a useful tool for differentiating patients with arytenoid immobility due to neoplastic involvement (cT3/pT3) from those in which arytenoid fixation has inflammatory causes (cT3/pT2). Indeed, this can greatly influence treatment choice, favoring conservative approaches aimed at preserving laryngeal function, as well as requiring elective management of neck lymph nodes or predicting postoperative adjuvant treatments [4,13–16]. However, the present study has some drawbacks that should be taken into consideration. First of all, it involved a retrospective analysis carried out on a small subset of clinically homogeneous patients who were evaluated, treated, and histopathologically analyzed by the same multidisciplinary team. Due to the retrospective nature of the study, histopathological analysis was not performed in a way to allow a truly comprehensive subsite by subsite matching. In the future, a structured reporting model will be developed in order to prospectively collect a higher number of clinical, histological, and radiological details. This could allow for further prognostic subcategories to be identified and for the development of novel, personalized treatment approaches. Nevertheless, we strongly believe that a detailed MR analysis of CAU and PLC neoplastic involvement represents an essential step in patient work-up to guide treatment selection towards surgical options like transoral laser microsurgery, OPHLs, and TL or organ preservation protocols.

5. Conclusions This retrospective analysis confirms the possibility of preoperatively assessing, with good diagnostic accuracy, the actual PLC involvement in cT3 laryngeal SCC using state-of-the-art MR protocols and surface coils. A detailed evaluation of the three-dimensional local extent of disease within the larynx will definitely allow for the fine-tuning of the therapeutic approach, balancing the Cancers 2019, 11, 67 10 of 11 need for more aggressive treatments in the subset of real cT3/pT3 patients with PLC involvement, and sparing undue therapeutic morbidity to those with less critical local extension (cT3/pT2).

Author Contributions: Conceptualization, M.R., A.P., F.D.B., N.M., C.P. (Carlotta Pessina), and C.P. (Cesare Piazza); Methodology, M.R. and D.F.; Validation, M.R., A.P., F.D.B., and C.P. (Cesare Piazza); Formal Analysis, M.R.; Investigation, M.R., C.P. (Carlotta Pessina), S.B., D.F., and R.M.; Data Curation, C.P. (Carlotta Pessina) and N.M.; Writing—Original Draft Preparation, M.R., A.P., and F.D.B..; Writing—Review & Editing, D.F., P.N., R.M., and C.P. (Cesare Piazza); Supervision, P.N., R.M., and C.P. (Cesare Piazza). Funding: This research received no external funding. Acknowledgments: We acknowledge Marco Ferrari for providing the anatomical section represented in Figure1. Conflicts of Interest: The authors declare no conflict of interest.

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