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Original Research—Otology and Neurotology

Otolaryngology– Head and Neck Surgery

Contemporary Management of Jugular Paragangliomas With Neural Preservation

2021, Vol. 164(2) 391–398 American Academy of Otolaryngology–Head and Neck

Surgery Foundation 2020 Reprints and permission:

sagepub.com/journalsPermissions.nav DOI: 10.1177/0194599820938660 http://otojournal.org

Nauman F. Manzoor, MD 1 , Kristen L. Yancey, MD 1 , Joseph M. Aulino, MD 2 , Alexander D. Sherry, MD 3 , Mohamed H. Khattab, MD 3 , Anthony Cmelak, MD 3 , William G. Morrel, MD 1 , David S. Haynes, MD, MMHC 1 , Marc L. Bennett, MD, MMHC 1 , Matthew R. O’Malley, MD 1 , James Netterville, MD 1 , George Wanna, MD 4 , and Alejandro Rivas, MD 1

Abstract Objectives. Management of jugular paragangliomas (PGL) has evolved toward subtotal resection (STR). The purpose of this study is to analyze neural preservation and adjuvant treat ment for long-term local control.

Received February 3, 2020; accepted May 26, 2020.

J ugular paragangliomas (PGL) are slow-growing vascu lar tumors that can involve various lateral skull base subsites with or without intracranial extension. Management of these tumors is highly complex and may include observation, radiation, or microsurgical resection. 1 Historically, these lesions were treated aggressively with gross total resection (GTR), with resultant high morbidity and even mortality. 2-4 Posttreatment lower cranial neuropa thy (LCN) usually manifests with profound dysphagia and dysphonia and confers significant functional morbidity. 5 More recently, subtotal resection (STR) has emerged as a sound alternative for a traditional, more aggressive resec tion. 6,7 Advantages include minimizing the risk of lower cra nial nerve dysfunction. When indicated, proponents of this approach often advocate for the use of salvage or adjuvant stereotactic radiation for optimal local control of tumor. Our group has previously reported on outcomes of STR in patients with advanced jugular PGL with preservation of lower cranial nerves. 8 Herein, we seek to examine our evolving contemporary experience in the management of jugular PGL and outline 1 Department of Otolaryngology–Head and Neck Surgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA 2 Department of Radiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA 3 Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee, USA 4 Department of Otolaryngology, New York Eye and Ear Infirmary, New York, New York, USA This article was presented at the AAO-HNSF 2019 Annual Meeting & OTO EXPO; September 15-18, 2019; New Orleans, Louisiana. Corresponding Author: Alejandro Rivas, MD, The Otology Group of Vanderbilt, Vanderbilt University Medical Center, 7209 Medical Center East South Tower, 1215 21st Avenue South, Nashville, TN 37232-8605, USA. Email: alejandro.rivas@vumc.org

Study Design. Retrospective chart review. Settings. Tertiary neurotology practice.

Subjects and Methods. Adults undergoing surgical treatment of jugular PGL between 2006 and 2019. Patients, disease, and treatment variables were collected retrospectively. Single predictor logistic regression was used to ascertain predictors of regrowth or need for salvage radiation. Results. A total of 41 patients (median age, 47 years; 76% female) were identified. Most patients presented with advanced stage disease (Glasscock-Jackson stage III-IV = 76%). Subtotal resection (STR) was performed in 32 (78%) patients. Extended STR (type 1) was the most commonly performed conservative procedure (n = 19, 59%). Postoperative new low cranial neuropathy (LCN) involving CN X and XII was rare (n = 3 and n = 1, respectively). Seventeen patients (41%) underwent postsurgical therapy for tumor regrowth or recurrence, including 15 patients who underwent adjuvant (n = 4) or salvage (n = 11) radia tion. Overall tumor control of 94.7% was achieved at a mean follow-up of 35 months. All patients treated with combined modality treatment had local control at last follow-up. Logistic regression identified no single predictor for postsurgical radiation treatment or salvage-free survival. Conclusion. Management of jugular PGL with a conservative approach is safe and effective with a low rate of new LCN def icit. Active surveillance of residual tumor with salvage radiation for growth results in excellent long-term tumor control. Keywords jugular paraganglioma, subtotal resection, neural preserva tion, infratemporal fossa

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Figure1. Subtotal resection (type 1, T1-weighed postcontrast). Large paraganglioma centered in the left jugular foramen (A). Tumor com ponent within the internal jugular vein (B). Postoperative imaging showing resection of most of the lesion (C).

predictors of successful local control using volumetric analy sis as well as preservation of swallowing and voice function.

these cases, disease in the jugular bulb was not resected ( Figure 3A-C ).

Radiation Linear accelerator-based stereotactic radiosurgery (SRS) or intensity-modulated radiotherapy (IMRT) was used either in the adjuvant or salvage settings after multidisciplinary review. All patients received pretreatment contrast-enhanced thin-slice magnetic resonance imaging or magnetic resonance angiogra phy, which was subsequently co-registered with high-resolution computed tomography (CT) for radiation treatment–planning purposes and for contour delineation. Brainlab iPlan (Brainlab AG, Munich, Germany) or Eclipse software was used for dosi metric planning and evaluation. Earlier patients were treated with frame-based immobilization using a Clinac 4 (Varian, Palo Alto, CA), while more recent patients were treated with mask-based (aquaplast) immobilization on a Novalis TX linear accelerator (Varian). ExacTrac orthogonal imaging was used to confirm proper patient alignment during treatment (Brainlab AG, Munich Germany). Volumetric Analysis Pre- and posttreatment enhanced CT and magnetic resonance studies were used to calculate tumor volumes (cm 3 ) and linear dimensions using semiautomated manual tracing of tumor margins using syngo.via postprocessing, thin-client software (Siemens, Erlangen, Germany, version VB30, MM Reading Workflow) by an experienced neuroradiologist (J.M.A.). For volume measurements, the tumor was segmen ted using the volume of interest freehand manual tracing tool in the optimal axial or coronal plane, and the volume was calculated by the software ( Figure 4A , B ). Jugular PGL have complex geometrical shapes and can have intraluminal disease in the venous sinus and jugular bulb ( Figure 4C ). For linear dimensions, the largest dimension in the axial plane was measured using a linear caliper, followed by the largest perpendicular dimension on the same image slice. Similarly, the largest craniocaudal dimension was measured in the coronal plane.

Methods After institutional review board approval (Vanderbilt University Medical Center, IRB 181441), retrospective chart review was carried out to extract data related to patient, disease, and treatment factors. Patient variables included age, gender, laterality, family history, synchronous PGL, prior surgical or radiation treatment, and presentation. Tumor characteristics and treatment records were reviewed including staging (Glasscock-Jackson), 1 preoperative embolization, surgical approach, extent of resection (EOR), adjuvant or salvage radiation, and final tumor control. Facial nerve function was documented using the House Brackmann (HB) grade. Lower cranial nerves (CN IX, X, XI and XII) were assessed at the time of initial presentation and after any intervention. Treatment-related complications (dys phagia requiring percutaneous gastrostomy tube [PEG], need for medialization laryngoplasty for new-onset CN X dys function, cerebrospinal fluid leak, or surgical site infection) were documented. Surgical Details Microsurgical resection was performed according to the stage of disease. In advanced disease, patients underwent a combined approach by neurotology and head and neck surgi cal teams via an infratemporal fossa type A (IFTA) approach with or without facial nerve mobilization. Three types of STR were performed. Extended STR (type 1) was used when the aim was to remove the middle ear, mastoid, cervi cal, and infratemporal fossa component while preserving the medial wall of the jugular bulb and pars nervosa ( Figure 1A-C ). Posterior fossa craniotomy-based STR (type 2) was used when the main objective was to decrease tumor burden in the posterior cranial fossa and decompress the brainstem ( Figure 2A-C ). Limited STR (type 3) was employed when middle ear and mastoid disease was removed using an otolo gic approach without any concomitant cervical approach. In

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Figure2. Subtotal resection (type II, T1-weighted postcontrast). Preoperative axial (A) and coronal (B) images show a large cerebellopon tine angle (CPA) component. Postoperative axial image (C) shows decreased mass effect on the brainstem and cerebellum.

Figure3. Subtotal resection (type III, computed tomography [CT] and T1-weighted postcontrast). Coronal CT (A) showing paraganglioma (arrow). Preoperative magnetic resonance imaging (B) showing tumor extending to the hypotympanum (arrow). Postoperative imaging (C) showing resection of the hypotympanic component.

Figure4. Preoperative (A) and postoperative (B) tumor volumes, highlighted in pink, after manual contouring and automated volume analy sis. In another patient (C), the tumor margin has been drawn manually. Jugalar foramen paraganglioma is often irregular in contour.

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Radiographic STR was defined as any postoperative contrast-enhancing tissue that is correlated with intraopera tive remnant location. Radiographic GTR was defined as an absence of any definitive evidence of residual or recurrent tumors on postresection, surveillance imaging. Statistical Analysis Descriptive statistics were used to summarize categorical variables and continuous variables. Continuous variables were tested for normalcy with the Shapiro-Wilk test, and those found to have a nonnormal distribution were described by median and interquartile range (IQR). Single predictor binary logistic regression models were used to assess poten tial predictors of post-STR tumor growth and the need for postsurgical radiation. Single predictor linear regression was used to evaluate the association of variables with continuous outcomes. Kruskal-Wallis test and Fischer’s exact test evalu ated clinicopathologic variables for association between cohorts. Single predictor Cox proportional hazards regression models were constructed to assess variables for association with time to salvage therapy. Proportionality was assessed for all covariates by the Kolmogorov-type supremum test with 1000 simulations and by graphing Martingale score residuals versus time. Salvage-free survival was analyzed by the Kaplan–Meier method. Multivariable analysis was not per formed because of the limited number of disease events. All confidence intervals were reported at 95%, and all P values were reported as two-sided, with an alpha level of .05. All statistical analyses were performed using SAS ver sion 9.4 (SAS Institute Inc., Cary, NC), and plots were gen erated using Prism version 7 (GraphPad Software, La Jolla, CA). Results Between July 2006 and March 2019, 41 patients (median age 47, 76% female) were retrospectively identified ( Table 1 ). Seven patients had previously undergone treatment at other institutions at the time of presentation, including 4 (10%) with prior microsurgical resection and 3 (7%) having received radiation. Four patients (10 %) had a family history of PGL, and 10 (24%) patients had another synchronous PGL. Pulsatile tinnitus (73%) and hearing loss (80%) were the most common presenting symptoms. Most patients pre sented with advanced-stage disease as categorized by both Glasscock-Jackson (76% with stage III and IV; Table 1 ). Surgical Approach and EOR Most surgical patients (78%) underwent STR ( Table 2 ). Extended STR (type 1) was employed in 19 (59%) patients in the STR cohort. All patients in the GTR cohort had a combined neurotologic and cervical approach, compared with 16 (50%) patients in the STR cohort who underwent isolated neurotologic procedure. The most common neuroto logic procedure was IFTA, with fallopian bridge technique (39%), followed by tympanomastoidectomy (26%). Twenty one patients in the STR cohort had both pre- and postoperative imaging of sufficient quality to generate actuarial volumetric

Table1. Patient Demographics and Disease Characteristics.

Median/ incidence

Variable

IQRor%

Age (years)

47 31

35-59

Gender (female) Prior surgery Prior radiation

76% 10%

4 3 4 3 4 4 3 2

Family history of PGL

10% 24%

Other PGL

Contralateral jugular Ipsilateral carotid body Contralateral carotid body

10% 10%

Ipsilateral vagal Other location

7% 5%

Most common symptoms at presentation Pulsatile tinnitus

30 33 11

73% 80% 26% 22% 32%

Hearing loss Disequilibrium

Otalgia

Aural fullness

Glasscock-Jackson staging I

2 8

20% 27% 49%

III IV

11 20

Laterality Right

22 19 35

54% 46%

Left

Postoperative follow-up (months)

10-87

Abbreviations: IQR, interquartile range; PGL, paraganglioma.

data. The median EOR based on volumetric analysis was 36% (0%-96%). On average, EOR was smallest for patients following type 3 STR, with a median EOR of 17% (IQR 4%-29%). In contrast, the median EOR following type 1 STR was 48% (IQR 28%-68%) and 64% (IQR 55%-72%) after type 2 STR. However, the type of STR was not statisti cally correlated with EOR ( p = 0.06). Table 3 expands on the clinical and tumor parameters between extended STR (type 1) and Type 2/3. There was no difference in terms of initial tumor stage (Glasscock-Jackson) or preoperative tumor volume between cohorts ( Table 3 ). Tumor Control The median postoperative follow-up was 35 months (IQR, 10-87 months). Fifteen patients in the STR (46.9%) had tumor growth following initial surgery (type 1, 68%; type 2, 20%; type 3, 12.5%). One patient had recurrence following GTR (11.1%). Binary logistic regression demonstrated STR (type 1) to be associated with risk of tumor regrowth com pared with type 2 and 3 (odds ratio [OR] 11.9, 95% confi dence interval [CI] 1.99-71, p = 0.007). There were no other significant clinical, disease or treatment-related predictors for post-STR tumor growth ( Table4 ).

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Seventeen patients (41%) underwent postsurgical therapy, including radiation in 13 patients (77%), salvage surgery in 2 patients (12%), and salvage surgery followed by radiation in 2 patients (12%). Radiation was planned preoperatively to be delivered in the adjuvant setting in 4 cases, although most radiation was in the salvage setting (n = 11). Of patients treated with radiation, 12 (80%) were treated with SRS and 3 (20%) were treated with IMRT ( Table 2 ). The median SRS dose was 25 Gy (IQR, 18-25 Gy) delivered in a median of five fractions (IQR, 2-5 fractions) with a median biologic equivalent dose (BED) of 68 Gy (IQR, 67-79 Gy). The median IMRT dose was 45 Gy (IQR, 45-54 Gy) delivered in a median of 25 fractions (IQR, 25-27 fractions) with a median BED of 72 Gy (IQR 72-90 Gy). The median time from surgery to salvage therapy was 49 months (IQR, 8-23 months; Figure 5 ). Binary logistic regression did not demonstrate any significant clinical, dis ease, or surgical predictors of the need for radiation after GTRor STR ( Table 4 ). Cox proportional hazards regression models did not reveal any significant association between single variable predictors and post-STR salvage-free survival ( Figure5 ). All patients who received combined modality treatment (surgery plus adjuvant or salvage therapy) had controlled disease at the time of last follow-up; therefore, no analyses were done to analyze for predictors of adjuvant/salvage ther apy success. STR and Cranial Nerve Outcomes Single predictor binary logistic regression did not find any statistically significant associations between STR type and postoperative cranial neuropathy. Type 1 STR was not asso ciated with increased risk of new-onset cranial neuropathy compared with type 2, type 3, or type 2 and 3 collectively (OR 1.06, 95% CI 0.16-6.94, P = .95). Lower Cranial Nerve Outcomes At presentation, the most common LCN involved was CN XII (n = 11, 27%), followed by CN X (n = 10, 24%; Table 5 ). New postoperative LCN was uncommon, involving CN

Table2. Details of Microsurgical and Radiation Treatment.

Median/ incidence

IQR/ frequency

Variable

Grouping GTR with no preop CN deficits GTR with preop CN deficits STR with no preop CN deficits STR with preop CN deficits

6 3

15%

22 10

54% 24%

Indications for surgery Tumor growth

17% 39% 20% 39% 51%

Cranial nerve involvement

Other

Patient preference

16 21

Presurgical embolization

Type of STR Type 1: Extended STR with LC preservation

59%

Type 2: Posterior fossa decompression

16%

Type 3: Limited middle ear STR

25%

Neurotology procedure ITF with FN transposition ITF with fallopian bridge Tympanomastoidectomy

10% 39% 26%

16 11

TEES

3 7

Posterior fossa craniotomy

17%

Radiotherapy technique Stereotactic radiosurgery

80% 20%

Intensity-modulated radiotherapy Radiation dose Stereotactic radiosurgery dose (Gy) Biologically effective dose (Gy) Intensity-modulated radiotherapy dose (Gy) Biologically effective dose (Gy)

25 68 45

18-25 67-79 45-54

72-90

Abbreviations: CN, cranial nerve; FN, facial nerve; IQR, interquartile range; ITF, infratemporal fossa; GTR, gross total resection; LCN, lower cranial neu ropathy; PGL, paraganglioma; STR, subtotal resection; TEES, transcanal endoscopic approach.

Table3. Clinical and Radiographic Differences in STR Cohorts.

Type 1 STR

Type 2/3 STR

Variable

Median/incidence

IQRor %

Median/incidence

IQRor%

Age (years)

35-60

34-66

.37 .21

Glasscock-Jackson Staging

I-II

3 5

16% 26% 58%

6 2 5

46% 15% 38%

III IV

11 12

Preoperative tumor volume (cm 3 ) Postoperative tumor volume (cm 3 )

6.7-27.7 2.6-16.6

5.7 5.4

3.4-27.1 2.6-8.2

.18 .88 .16

4.2

EOR (%)

47.5

25-69

5-46.7

Abbreviations: EOR, extent of resection; IQR, interquartile range; STR, subtotal resection.

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Table 4. Single Predictor Models Evaluating Tumor Growth Following Resection and Requirement for Radiation by Binary Logistic Regression With Odds Ratio (OR), 95% Confidence Interval (95% CI), and P Value.

Recurrence following surgery

Radiation

Predictor

95%CI

Age

0.98 3.29 0.49 0.57 1.38 0.45 1.38

0.93 0.60 0.05 0.10 0.38 0.08 0.38

1.02

.32 .17 .55 .54 .62 .37 .62

1.01 1.47 0.55 1.38 2.57 1.05 1.07

0.97 0.32 0.05 0.26 0.69 0.21 0.29

1.06 6.83 5.79 7.19 9.55 5.19 3.92

.55 .62 .62 .71 .16 .95 .92 Ref .14 .61 .84

Female gender

PGL family history

5.16

Indication

Tumor growth CN involvement

3.38 4.98 2.59 4.98

Other

Patient preference

GJ staging I-II

Ref

III IV

0.56 1.23 1.39

0.09 0.26 0.40

3.52 5.73 4.92

.39 .45 .61

0.22 0.67 1.14

0.03 0.15 0.32

1.60 3.08 4.08

Embolization

STR type Type 1

11.9

1.99

.007

2.50

0.57

.23 Ref

Type 2/3

Ref

Preoperative

Tumor volume

1.02

0.96

1.10

.50

0.99

0.93

1.05

.72

Postoperative

Tumor volume

1.00 1.00

0.92 0.97

1.09 1.03

.97 .96

1.05 0.97

0.96 0.94

1.16 1.01

.31 .10

EOR

Abbreviations: EOR, extent of resection; GTR, gross total resection; IQR, interquartile range; PGL, paraganglioma; STR, subtotal resection.

Table 5. Frequency of Pre- and Posttreatment Lower Cranial Nerve Neuropathy.

Cranial Nerve

Preoperative, n (%)

Postoperative, n (%)

5 (12)

10 (24)

3 (7)

4 (10)

5 (12)

XII

11 (27)

1 (2)

Facial Nerve Outcomes Six patients (15%) had CN VII weakness at presentation. Preoperatively, HB grade was 1 (n = 35, 85%), 3 (n = 3, 7%), or 6 (n = 3, 7%). All 3 patients with HB grade 6 required intraoperative CN VII sacrifice. Of the 35 patients with preoperative HB grade 1, 32 had postoperative facial nerve examinations documented between 3 and 12 months of follow-up. A total of 29 patients (91%) continued to have HB grade 1, whereas 2 patients (6%) had HB grade 2 and 1 patient (3%) had HB grade 3. Complications Two patients had cerebrospinal fluid leaks (n = 2, 5%), which required operative repair. One patient had a pseudo meningocele (n = 1, 2%), which resolved with the use of

Figure5. Kaplan-Meier plot of salvage therapy-free survival following subtotal resection. 95% confidence intervals are represented by dotted lines. Number of patients at risk are displayed below the x -axis.

IX (n = 5) and XI (n = 5) in 12% of cases. CN X (n = 3) and XII (n = 1) were also rarely affected following surgery. Ten patients (24%) underwent medialization laryngoplasty for voice rehabilitation, but only 2 (5%) of these were for new, postoperative CN X dysfunction. Five patients required intervention for dysphagia, either undergoing placement a nasogastric (n = 1, 2%) or PEG (n = 4, 10%) tubes.

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lumbar drain. Two patients developed surgical site infections (5%). There were no cases of meningitis, intracranial bleed ing, or mortality. Discussion Jugular PGL are the most common tumors involving the jugular foramen, and management requires a complex recon ciliation of multiple patient and disease variables. 1,3 While GTR has historically advocated for complete resection of tumor, its resultant morbidity has given way to more conser vative approaches for management of jugular PGL. 1,6-9 STR has yielded a lower incidence of new-onset LCN. In cases of remnant growth or recurrence, salvage radiation can be used for optimal control of tumor, with resultant excellent local control in most patients. 8-10 STR can be tailored to the extent of disease and patient goals. Extended STR is usually employed for high-volume disease with a significant cervical and infratemporal fossa component. The principle of these resections is to remove the disease lateral to the medial wall of the jugular bulb while preserving lower cranial nerves ( Figure 1A-C ). Limited STR is usually employed in the removal of the middle ear and mastoid tumor component or for the targeted removal of posterior fossa tumor in cases of significant intra cranial extension with brainstem compression ( Figures 2 and 3 ). Various lateral and posterolateral skull base approaches can be used for management of the intracranial component. In the presence of functional lower cranial nerves, utmost care is taken to preserve the cisternal component of the lower cra nial nerves. Patients with a limited volume of disease in the middle ear can be treated either with a transcanal endoscopic approach or with a tympanomastoidectomy with extended facial recess in the setting of substantial middle ear and mastoid disease. The jugular bulb is not resected in these limited STR approaches. Instead, surgery seeks to control debilitating pulsa tile tinnitus and improve conductive hearing loss by the tar geted removal of middle ear disease In this study, we found that STR provides effective dis ease control and allows for individualized treatment strate gies tailored to the extent and volume of disease. Most patients in the STR cohort received a combined skull base and cervical approach, optimizing tumor access while pre serving lower CNs. In select cases, limited resection of middle ear and mastoid PGL components was performed. Patients presenting with significant intracranial tumor invol vement also benefitted from a multidisciplinary approach with microsurgical removal of the intracranial component to relieve brainstem compression. There was no difference in terms of new-onset cranial neuropathies between different types of STR. In the present study, we found lower rates of new lower cranial neuropathies following STR compared with those reported after GTR. 4,5,11 Specifically, postoperative neuropa thy involving CN X and XII occurred in 3 (7%) and 1 (2%) patients, respectively. In a previously reviewed cohort from our institution (1971-2006, n = 238), 90% of patients

underwent GTR, with a 60% LCN rate after surgery (IX = 40%, X = 24%, XI = 26%, XII = 21%). 3 In one of the largest operative series of jugular PGL treated primarily with GTR, Bacciu et al 5 reported LCN rates between 22.8% and 50%, similar to other large institutional series. 5 Overall, there was 100% local control in patients treated with combined modality treatment. Two patients with single modality treatment were awaiting salvage treatment at the time of study conclusion. Type 1 STR was associated with increased risk of regrowth, although there was no statisti cally significant differences in terms of preoperative and postoperative tumor volumes or disease stage (Glasscock Jackson) between cohorts. There was no difference in the need for adjuvant radiation or salvage therapy–free survival between types of STR. We did not use disease-free interval or progression-free survival analysis to limit immortal time bias, which is inherent in this cohort treated with multiple and variable techniques at heterogenous time points. EOR was also not a significant predictor of regrowth or need for salvage radiation, but this may reflect a statistical limitation related to the present analysis usage of an actuarial volumetric estimation of EOR. In contrast, Wanna et al 1 pre viously noted regrowth in cases that had more than 20% of residual tumor using an ellipsoid-based estimation of tumor volume. 1 Further high-powered studies contrasting EOR using different methods of volumetric estimation will yield more insight about this predictor. The role of radiation (stereotactic or IMRT) therapy in a salvage or adjuvant setting has recently been reviewed with resultant excellent local control of disease and minimal associated toxicity. 12 Previous reports have also highlighted STR with targeted radiation for optimal tumor The present study reports outcomes of conservative surgical approaches for neural preservation in jugular PGL. This is the first study that uses actuarial volumetric analysis of these complex tumors to ascertain predictors of tumor regrowth and need for postsurgical intervention. Major limitations include the inability to assess the preintervention growth rate as most of these lesions presented at advanced stage and lacked preoperative, serial imaging. There was also lack of genetic information (presence and type of succinate dehydro genase mutation). We were also able to analyze volumetric data for only 21 of the 32 patients who underwent STR, hence limiting the sample size in each type of STR. The rel atively small sample size prevented the use of multivariate regression. Larger pooled studies with meta-analysis are needed to analyze these predictors. Conclusion Conservative surgical management of jugular PGL with tar geted STR based on the extent and location of tumor yields in lower new-onset LCN. Local tumor control can be achieved with radiation therapy in both salvage and adjuvant settings at short-term follow-up. Studies with longer control with minimal morbidity. 6,9 Strengths and Limitations

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follow-up as well as multi-institutional collaborations with increased sample size will elucidate predictors of regrowth and need for salvage therapies. Author Contributions Nauman F. Manzoor , conception, data acquisition and analysis, manuscript drafting, and critical review; Kristen L. Yancey , con ception, data acquisition and analysis, manuscript drafting, and critical review; Joseph M. Aulino , data acquisition and analysis, manuscript drafting, and critical review; Alexander D. Sherry , data acquisition and analysis, manuscript drafting, and critical review; Mohamed H. Khattab , data acquisition and analysis, manuscript drafting, and critical review; Anthony Cmelak , conception, data analysis, manuscript drafting, and critical review; William G. Morrel , data acquisition and analysis, manuscript drafting, and criti cal review; David S. Haynes , conception, data analysis, manuscript drafting and critical review; Marc L. Bennett , conception, data analysis, manuscript drafting, and critical review; Matthew R. O’Malley , conception, data analysis, manuscript drafting, and criti cal review; James Netterville , conception, data analysis, manuscript drafting, and critical review; George Wanna , conception, data anal ysis, manuscript drafting, and critical review; Alejandro Rivas , con ception, data analysis, manuscript drafting, and critical review. Disclosures Competing interests: David S. Haynes, consultant for Med-El, Advanced Bionics, Stryker, and Cochlear; Alejandro Rivas, consul tant for Med-El, Advanced Bionics, Cochlear, Grace Medical,

management of tympanojugular paragangliomas. Head Neck . 2016;38(6):871-885. 3. Kaylie DM, O’Malley M, Aulino JM, Jackson CG. Neurotologic surgery for glomus tumors. Otolaryngol Clin North Am . 2007; 40(3):625-649. 4. Jackson CG, McGrew BM, Forest JA, Netterville JL, Hampf CF, Glasscock ME III. Lateral skull base surgery for glomus tumors: long-term control. Otol Neurotol . 2001;22(3):377-382. 5. Bacciu A, Medina M, Ait Mimoune H, et al. Lower cranial nerves function after surgical treatment of Fisch Class C and D tympanojugular paragangliomas. Eur Arch Otorhinolaryngol . 2015;272(2):311-319. 6. Miller JP, Semaan MT, Maciunas RJ, Einstein DB, Megerian CA. Radiosurgery for glomus jugulare tumors. Otolaryngol Clin North Am . 2009;42(4):689-706. 7. Cosetti M, Linstrom C, Alexiades G, Tessema B, Parisier S. Glomus tumors in patients of advanced age: a conservative approach. Laryngoscope . 2008;118(2):270-274. 8. Wanna GB, Sweeney AD, Carlson ML, et al. Subtotal resection for management of large jugular paragangliomas with func tional lower cranial nerves. Otolaryngol Head Neck Surg . 2014;151(6):991-995. 9. Miller JP, Semaan M, Einstein D, Megerian CA, Maciunas RJ. Staged Gamma Knife radiosurgery after tailored surgical resec tion: a novel treatment paradigm for glomus jugulare tumors. Stereotact Funct Neurosurg . 2009;87(1):31-36. 10. Jansen TTG, Kaanders J, Beute GN, Timmers H, Marres HAM, Kunst HPM. Surgery, radiotherapy or a combined modality for jugulotympanic paraganglioma of Fisch class C and D. Clin Otolaryngol . 2018;43(6):1566-1572. 11. Moe KS, Li D, Linder TE, Schmid S, Fisch U. An update on the surgical treatment of temporal bone paraganglioma. Skull Base Surg . 1999;9(3):185-194. 12. Anderson JL, Khattab MH, Anderson C, et al. Long-term out comes for the treatment of paragangliomas in the upfront, adju vant, and salvage settings with stereotactic radiosurgery and intensity-modulated radiotherapy. Otol Neurotol . 2020;41(1): 133-140.

Stryker, Cook Medical. Sponsorships: None. Funding source: None.

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Superior semicircular canal dehiscence in relation to the superior petrosal sinus: a potential cause of pulsatile tinnitus Z. Liu a , d , * , W. Bi b , d , J. Li a , Q. Li a , C. Dong c , P. Zhao c , H. Lv c , Z. Wang c , ** a Capital Medical University, Beijing Tongren Hospital, No. 1 Dong Jiao Min Street, Dongcheng District, Beijing, 100730, China b Shandong Medical Imaging Research Institute, No. 324 Jing 5 Road, Jinan, 250021, China c Capital Medical University, Beijing Friendship Hospital, No. 95 Yongan Road, Xicheng District, Beijing, 100050, China

AIM: To examine the association between superior semicircular canal dehiscence (SSCD) and pulsatile tinnitus (PT). MATERIALS AND METHODS: Two SSCD groups included 408 unilateral persistent PT pa tients, and 511 controls undergoing head and neck dual-phase contrast-enhanced computed tomography (DP-CECT) for reasons other than PT. The prevalence of type I (no the superior petrosal sinus running through the dehiscence) and type II (superior semicircular canal dehiscence in relation to the superior petrosal sinus) SSCD was analysed using chi-square test. RESULTS: SSCD was identi fi ed in 5.1% (21/408) of PT ears, signi fi cantly different from 2% (8/ 408) of non-PT ears and 0.7% (7/1022) of controls. There was no signi fi cant difference in SSCD prevalence between non-PT ears in the PT group and controls. In the PT group, 15/21 ears were type II SSCD; 6/21 ears were type I. Fifteen combined non-PT and control ears with SSCD included two type II and 13 type I SSCD. The prevalence of type II SSCD in PT ears was signi fi cantly higher than that of non-PT ears in both groups, and the prevalence of type I SSCD in PT ears was similar to that of non-PT ears in both groups. CONCLUSION: Compared with type I SSCD, there may be a causal relationship between type II SSCD and PT. 2015 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

article information

Article history: Received 29 November 2014 Received in revised form 8 April 2015 Accepted 28 April 2015

Introduction

Pulsatile tinnitus (PT), a subtype of tinnitus, is the perception of a rhythmical noise that is synchronous with the patient ’ s heartbeat. It is a serious public health problem and frequently induces anxiety and depression, and some times suicide. Most of these distressed patients are willing to accept the risks of surgery for their disorder. Because management is ideally directed at treating the cause of PT, accurate diagnosis is imperative.

* Guarantor and correspondent: Z. Liu, Capital Medical University, Beijing Tongren Hospital, No. 1 Dong Jiao Min Street, Dongcheng District, Beijing,100730, China. Tel.: þ 86 010 58268064. ** Guarantor and correspondent: Z. Wang, Capital Medical University, Beijing Friendship Hospital, No 95 Yongan Road, Xicheng District, Beijing 100050, China. Tel.: þ 86 010 63131437 E-mail addresses: lzhtrhos@163.com (Z. Liu), cjr.wzhch@vip.163.com (Z. Wang). d Co- fi rst authors: Z. Liu and W. Bi.

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matrix;22 22cmto24 24cm fi eld of view; 0.75 s rotation time; and 64 0.625 mm collimation. A bolus-tracking program (Trigger Bolus software; region of interest area, 200mm 2 ; trigger point, ascending aorta; trigger threshold, 120 HU) was used. Iodinated non-ionic contrast material (iopamidol, 370 mg iodine/ml; BRACCO, Shanghai, China) was administered intravenously using an injection syringe at a rate of 5 ml/s, at a dose of 60 ml/kg, based on the pa tient ’ s weight. The arterial phase was performed in a cephalocaudal direction and venous phase was performed in the opposite direction after 8 s. Axial, coronal, and obli que sagittal planes paralleling to the superior semicircular canal were reconstructed in a workstation to evaluate the arterial and venous systems with narrower settings (width, 700 HU; level, 200 HU), and the temporal bone with bone window settings (width, 4000 HU; level, 700 HU). The section thickness was 1 mm without a gap. The CT images were reviewed by two radiologists with 13 and 11 years ’ experience, respectively, and the fi ndings were reached by consensus. These radiologists were blin ded to the clinical history and radiological impressions at the time of study. During the analysis of the bony labyrinth of the superior semicircular canal, three radiological pat terns were distinguished. A complete roof of the superior semicircular canal was considered as the normal pattern. SSCD was classi fi ed into two types: type I was characterised by bony dehiscence of the superior semicircular canal without the superior petrosal sinus running through, and type II was characterised by the superior petrosal sinus running through the dehiscence in the superior semi circular canal. Chi-square tests and SPSS for Windows (version 11.0; SPSS, Chicago, IL, USA) were used to analyse the data. Fisher ’ s exact test was used when the sample size was deemed too small. First, the SSCD radiological frequency distribution was compared between sides or genders of the controls and between the PT group and controls. Second, the radiological frequency distribution of type I and type II SSCD in PT ears was compared with that in non-PT ears in the PT group and controls. All hypothesis tests were two sided using a 0.05 signi fi cance level. Within the controls, SSCD was identi fi ed in 0.4% of left ears (2/511 sides) and 1% of right ears (5/511 sides). Five of 336 male patients and one of 175 female patients pre sented with SSCD, with one male patient having bilateral SSCD. No signi fi cant difference was found in SSCD preva lence between sides or genders ( p ¼ 0.452 and p ¼ 0.669, respectively). Of the 408 PT patients, SSCD was identi fi ed in 5.1% of PT ears (21/408) and 2% of non-PT ears (8/408) with a Image interpretation Statistical analysis Results

PT has numerous causes including arterial, venous, and non-vascular. 1 e 6 Superior semicircular canal dehiscence (SSCD) has been reported as one cause of PT 1,7 15 ; however, most SSCD patients do not present with PT symptoms and instead, present only with vertiginous symptoms, oscil lopsia, and rotatory and vertical nystagmus following loud noises (SSCD syndrome). 16 e 26 It remains unclear whether there are differences in SSCD patients with and without PT. Various imaging strategies have been proposed and continue to evolve to investigate the causes of PT. Compared with promising results from dual-phase contrast-enhanced computed tomography (DP-CECT), which has the advantage of demonstrating artery, venous, soft tissue, and temporal bone in a single study, 27 high-resolution CT (HRCT) and magnetic resonance imaging (MRI) used in previous studies have limitations. The aim of the present study was to investigate the relationship between SSCD and PT, and to determine the characteristics of SSCD patients with PT based on DP-CECT image analysis in a large patient population. Similar to previous studies, it was hypothesised that SSCD is a cause of PT. The Institutional Review Board for Human Subjects Research of Capital Medical University, Beijing Tongren Hospital, Beijing Friendship Hospital, and Shandong Medical Imaging Research Institute approved this study and informed consent was obtained from all patients. Two groups were evaluated for radiographic evidence of SSCD and the rela tionship between the dehiscence and superior petrosal sinus. The PT group included all patients with persistent unilateral PT between May 2008 and Jan 2013. Four hundred and eight patients were identi fi ed, 336 were female and 72 were male with a mean age of 45 13 years (range 17 e 79 years). One hundred and seventy-two patients had left-sided PT and 236 had right-sided PT. The median PT duration was 19 months (range 10 days to 36 years). After follow-up, the PT remained unchanged in 302 patients, gradually aggravated in 103 pa tients, and decreased slightly in the remaining three patients. Among 937 consecutive patients with sinonasal or orbital tumours, or orbital trauma who did not present with a history of tinnitus and underwent DP-CECT between May 2008 and January 2013, 511 patients were identi fi ed as controls, after excluding patients with low-quality images, brain or temporal bone surgery, and temporal bone fracture. The controls comprised 336 men and 175 women, with a mean age of 48 years (range 10 e 86 years). CT technique DP-CECT imaging was performed on a 64-section mul tidetector CT system (Brilliance 64; Philips, Best, The Netherlands). CT data acquisition spanned the vertex to the sixth cervical level. The imaging parameters were as fol lows: 100 kV and 250 mAs/section; 0.891 pitch; 512 512 Materials and methods Patients

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signi fi cant difference in the prevalence of SSCD among the PT ears, non-PT ears in the PT group, and controls ( p < 0.0001). The prevalence of SSCD in PT ears was signi fi cantly higher compared with controls and non-PT ears in the PT group ( p < 0.0001 and p ¼ 0.014, respectively); how ever, the prevalence of SSCD was not statistically different when comparing non-PT ears in the PT group with controls ( p ¼ 0.043 < 0.017). Based on the DP-CECT images, 15 PT ears and two non-PT ears were identi fi ed as type II SSCD (Fig 1). Type I SSCD was seen in six PT ears and 13 non-PT ears (Fig 2). The preva lence of type I and type II SSCD was signi fi cantly different between PT ears in the PT group and non-PT ears in both groups ( p < 0.0001). The prevalence of type II SSCD in PT ears was 3.7%, which was signi fi cantly higher than that of non PT ears (0.1%), and the prevalence of type I SSCD in PT and non-PT ears was similar (1.5% and 0.9%, respectively). The aim of the present study was to evaluate the different imaging characteristics of SSCD with and without PT. The data show the prevalence of type II SSCD in PT ears was signi fi cantly higher than that in non-PT ears in both the PT group and controls, and the prevalence of type I SSCD was similar among the PT ears and non-PT ears, which suggest that SSCD induces PT only when the superior petrosal sinus runs through the dehiscence site. In another words, the su perior petrosal sinus running through the dehiscence may be the essential condition for SSCD to induce PT. The pathological mechanism of SSCD in PT remains unclear 1,7 e 15 . The present fi ndings imply that there may be a causal relationship between type II SSCD and PT, which suggest the pulsation of the superior petrosal sinus would be transmitted to the cochlea through the damaged cortical plate of the superior semicircular canal, inducing pressure Discussion

fl uctuations in the cochlear lymph stimulating the spiral organ and converting the pulse into neural impulses that are experienced as PT. For type I SSCD ears, no pulsation is generated in the cochlear because the superior petrosal si nus is far from the dehiscence. For type II SSCD in non-PT ears, vessel pulsation may be too small to stimulate the spiral organ and induce PT. Although researchers debate whether SSCD is a devel opmental or congenital anomaly 11,18 , all cases developed PT in late middle age in the present study, suggesting that congenital type II SSCD is unlikely. Furthermore, dehiscence in all type II SSCD cases is proximal to the superior petrosal sinus suggesting that dehiscence may be caused by chronic forceful fl ow against the bony plate of the superior semi circular canal leading to gradual thinning of the cortical plate and eventual bony defect formation. The prevalence of the superior petrosal sinus running through dehiscence of the superior semicircular canal in PT ears in the present study was 3.7% (15/408). DP-CECT was used as the primary and initial survey method for radiological investigation in patients with PT at our institution (Neuroradiology Division, Department of Radiology, Emory University School of Medicine, Atlanta). Compared with combined CT angiography and venography with 100 ml contrast medium injected at 3 e 4 ml/s and a fi xed delay of 25 s using contemporary multisection CT, 28 DP-CECT not only has the advantage of demonstrating arterial, venous, skull base, and middle-ear diseases in a single study, but the arterial phase CT is an effective screening tool for dural arteriovenous fi stula. CT images reconstructed with bone algorithms best identify the su perior petrosal sinus running through dehiscence in the superior semicircular canal in the venous phase, which can simultaneously clearly demonstrate the integrity of the cortical roof of the superior semicircular canal and the course of the superior petrosal sinus.

Figure 1 CT images of a 53-year-old female patient with type II SSCD who experienced left-sided PT for 5 months. (a) Axial and (b) oblique sagittal CT images of the bony window show type II SSCD (arrow).

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Figure 2 CT images of a 46-year-old female patient with type I SSCD with no history of tinnitus. (a) Axial and (b) oblique sagittal CT images of the bony window show type I SSCD (arrow).

Limitations of this study include the retrospective design and the underlying cause of PT was not con fi rmed by treatment. To avoid these limitations, the radiological prevalence of SSCD was compared with and without the superior petrosal sinus running through in PT groups and controls to demonstrate the imaging characteristics of SSCD presenting with PT. In conclusion, the superior petrosal sinus running through the dehiscence may be essential for SSCD to induce PT.

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Con fl ict of Interest

The authors and authors ’ institutions have no con fl ictsof interest. This includes fi nancial or personal relationships that inappropriately in fl uence (bias) his or her actions (such relationships are also known as dual commitments, competing interests, or competing loyalties) within 3 years of the work beginning submitted

Acknowledgements

This work was supported by Grant 81171311 and 81371545 from the National Natural Science Foundation of China, and Grant 13JL03 from Capital Medical University.

References

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