Non-Functional Carotid Body Tumors in Patients Without Somatic Mutations May Be Considered for Non-Operative Management

Abstract

OBJECTIVES:

Carotid Body Tumors (CBT) are rare neuroendocrine paragangliomas which are typically asymptomatic and benign with a low rate of biochemical functionality. Historically, early surgical excision was recommended to prevent development of CBT-related complications. Yet, CBT resection can result in significant cranial nerve and vascular injuries. Recent work has shown successful primary observation without resection of non-carotid body, cranial paragangliomas with slow growth and low rate of neuropathies. We hypothesize that primary observation of CBT is safe and may be considered for the majority of CBT.

METHODS:

Retrospective cohort study of patients at a multi-hospital healthcare system with radiologic identification and/or diagnostic or procedural billing codes for CBT (2000–2019). Tumor size (greatest diameter), associated symptoms, and interventions were recorded at initial evaluation and throughout follow-up. Multivariable logistic regression investigated the risk of initial surgical resection

RESULTS:

108 patients (mean age, 59±19 years; 67% female) with 123 CBT (mean diameter 23±12mm; 52% right) were initially evaluated by otolaryngologists (51%), vascular surgeons (25%), neurosurgeons (8%), or other (16%) medical providers. 55 CBT were initially resected, 63 observed, and 5 irradiated. Initial resection was associated with younger age (aOR, 0.95 [95%CI, 0.92–0.97]), male sex (aOR, 4.82 [95%CI, 1.47–15.75]), and evaluation by a vascular surgeon (aOR, 6.17 [95%CI, 2.04–18.63]). Overall median follow-up was 4.7 (IQR, 2.6–9.1) years. Initially observed CBT were on average stable in size (mean 1±5mm/year), none became biochemically active, and 2 patients became symptomatic. At final follow-up, 63 (51%) surgical resection, 54 (44%) observation, 6 (5%) radiation therapy. Of the 63 surgically resected CBT, 5 (8.8%) patients had malignant CBTs of which 3 (60%) had known somatic mutations (polymerase epsilon [N=1], succinate dehydrogenase-D gene [N=2]). Thirty percent of CBT resections had in-hospital postoperative complications, notably including 1 stroke which occurred in an initially observed patient and 16 cranial nerve complications which all occurred in immediately resected patients. Three resected CBT locally recurred, only 1 of which had malignant pathology.

CONCLUSIONS:

Patients with newly diagnosed CBT require biochemical functionality and somatic mutation testing. In the absence of these findings, initial observation of CBTs with annual imaging and symptom monitoring may be considered an alternative to immediate resection which demonstrates a high risk of clinically meaningful postoperative complications.

INTRODUCTION

Carotid Body Tumors (CBT) are rare neuroendocrine tumors that were first described in 1743.^1,2 These cranial paragangliomas are typically asymptomatic, slow growing, and have a low rate of both malignancy and functional release of catecholamines.³ Intimately positioned between the internal and external carotid arteries, CBT co-localize with the facial, vagus, glossopharyngeal, and hypoglossal cranial nerves. The current CBT treatment recommendations include surgical excision to prevent the development of pain or cranial neuropathies.

CBT resection, however, results in postoperative complications in up to 50% of patients.⁴ Complications range from the rare, but devastating, stroke in approximately 4% of patients to permanent cranial nerve dysfunction in over 10% of patients, which includes complex autonomic, airway, and dysphagia related morbidities.^5,6 Larger tumors, closer to the skull base, with greater arterial encasement, resected by low volume surgeons confer an increased risk of blood loss and postoperative morbidity.^4,7 As such, preoperative embolization of external carotid branches has been explored but unfortunately does not consistently improve postoperative outcomes.^4,8,9

Although the classical teaching in vascular surgery is to resect CBT in those medically suitable for resection, multiple recent studies in the otolaryngology literature have shown that observation without resection of other cranial paragangliomas (i.e., glomus jugulare, tympanomastoid paragangliomas, and vagal body tumors) may optimize patient outcomes. Such paragangliomas have demonstrated slow tumor growth as well as low rates of pain and neuropathies.^10–12 As a result, the authors advocate a “wait and scan” primary strategy. In the face of high rates of postoperative CBT resection complications, we aim to catalog CBT treatment strategies and monitor long-term patient outcomes in a multi-hospital healthcare system providing both community and academic center care. We conducted a retrospective cohort study to evaluate our hypothesis that primary observation of CBT will be safe and may be considered for most tumors.

METHODS

We completed a retrospective cohort study of radiographically identified or surgically resected CBT at >20 community and academic hospitals in a large, western Pennsylvania healthcare system from January 1, 2000 to January 1, 2019. Our study was reviewed by the UPMC Quality Improvement Review Committee in accordance with Standard for Quality Improvement Reporting Excellence (SQUIRE) guidelines and therefore did not require institutional review board review or documented informed consent (QI1824).¹³ All data were abstracted following July 1, 2020 into a UPMC supported REDCap 8.2.1 (Vanderbilt University) database, allowing for a minimum of 18 months of potential follow up.

Data source.

The following data points were abstracted from the electronic heath record of patients with a CBT, including diagnostic evaluations, treatment course, and long-term follow-up. We collected diagnostic evaluations, including the medical and surgical specialty of the provider initially evaluating the CBT, patient demographic characteristics, general and neuroendocrine-specific comorbid conditions, both local (i.e., cranial neuropathies and other compressive symptoms) and systemic CBT symptoms potentially related to biochemical functionality (i.e., catecholamine excess), biochemical functional testing (i.e., laboratory catecholamine and metanephrine values of the urine and plasma), imaging and tumor characteristics including laterality, CBT somatic mutations, and family history. Following diagnosis, all imaging reports were reviewed, and tumor characteristics (i.e., maximal diameter and length) were recorded prior to any intervention. The annual growth rate was categorized as 1) increasing, growth by >2mm/year; 2) stable, change in size <2mm/year, 3) decreasing, regression by >2mm/year. The duration of follow-up was calculated from the date of diagnosis to the last documented patient encounter with the healthcare system, including death.

CBT identification.

We identified all CBT with two methods, 1) the presence of “carotid body tumor” or “carotid body paraganglioma” on any radiology reports for inpatient and outpatient imaging studies and 2) appropriate International Clinical Diagnosis Clinical Management and Procedure codes.⁷ Our primary study cohort included all CBT who underwent clinical evaluation. We excluded recurrent CBT without documented evaluation and treatment of the primary CBT. We also excluded patients with CBT who did not survive >30 days from CT diagnosis and were therefore unable to undergo CBT treatment. CBT were categorized by the initial treatment strategy at the clinician evaluation, 1) surgical resection, 2) observation, 3) radiation therapy. Both CBT surgical resection and radiation therapy were considered interventions. Patients were followed longitudinally and recategorized into a final treatment strategy, as needed.

Outcomes.

Outcomes were determined included complications related to the initial and final treatment strategies as well as mortality. For initially observed and radiated CBT, outcomes included local or systemic symptom progression. CBT size changes prior to any intervention were categorized based upon overall change in the diameter, 1) increasing, by growth of >2mm/year, 2) decreasing, by reduction of >2mm/year, or 3) stable. For initially and finally surgically resected CBT, outcomes included tumor pathology, reviewed operative reports, immediate postoperative complications observed exclusively during the hospital admission, and CBT recurrence.

Statistical analysis.

Continuous data were reported as mean (±standard deviation [SD]) or median (interquartile range [IQR]) for normally distributed and skewed variables. As appropriate, variables were compared with Kruskal-Wallis or with analysis of variance or student t-tests. Categorical variables were reported as frequency (percent) and compared with Chi-squared or Fisher exact testing. To investigate the association between CBT resection and baseline characteristics, those characteristics with clinical and statistical significance were included in a multivariable logistic regression model generating an adjusted odds ratio (aOR) and 95% confidence intervals (95%CI). Survival analysis was completed generating Kaplan Meier curve comparing initial resection and observation groups with log-rank testing. Data were analyzed from August 21, 2020 to March 1, 2021 with Stata 15.1 (StataCorp) and graphics were created using PRISM 9.0 (GraphPad). All comparisons were made with two-sided testing, and a P value of <.05 was considered significant.

RESULTS

We identified 108 patients (mean age, 59.4±19 years; 33% male; 87% White; Figure 1a) with 123 CBT (mean diameter 23±12mm, mean length 29±13mm; 52% right). The CBT were evaluated by otolaryngologists (51%), vascular surgeons (25%), neurosurgeons (8%), or non-surgical (16%) providers. The size of CBT did differ by the presenting provider evaluating the tumors with otolaryngologists (mean diameter 24±13mm, mean length 26±11mm) and vascular surgeons (mean diameter 26±11mm, mean length 33±12mm) evaluating the largest while neurosurgeons (mean diameter 13±5mm, mean length 24±7mm) and medical (mean diameter 19±8mm, mean length 31±20mm) providers evaluated smaller CBT (diameter P=.024, length P=.29). Initial treatments included 55 (45%) surgical resection, 63 (51%) observation, 5 (4%) radiation therapy. Overall, initial evaluation by surgical services (85%, N=104) more frequently resulted in initial surgical resection (50% vs 11%) and radiation therapy (100% vs 0%) than initial evaluations by medical specialists (P=.003). Notably, 89% (N=8/9) of neurosurgical evaluations resulted in initial observation, and one resulted in initial resection for a patient with known SDH-D somatic mutation (Table 1).

Figure 1.

Identification of patients with carotid body tumors and tumor treatment among the primary cohort

Abbreviations: CBT, carotid body tumor.

Panel A includes cohort identification on the patient level. Panel B demonstrates the initial treatment strategy and CBT that crossed over into a final treatment strategy.

Table 1.

Initial evaluation patient characteristics by initial treatment group

Factor	Initial Surgical Resection	Initial Observation	Initial Radiation Therapy	p-value
N	55	63	5
Baseline demographic data at initial evaluation
Age, mean (SD)	51.4 (17.6)	65.1 (18.0)	71.0 (6.0)	<.001
Female, No. (%)	27 (49.1%)	50 (79.4%)	5 (100.0%)	<.001
Race, No. (%)				<.001
Black	2 (3.7%)	10 (16.7%)	3 (60.0%)
White	52 (96.3%)	50 (83.3%)	2 (40.0%)
Body mass index, mean (SD)	29.1 (6.1)	29.0 (6.6)	44.9 (6.6)	<.001
Past medical history, No. (%)
Stroke	4 (7.3%)	10 (15.9%)	0 (0.0%)	.24
Hypertension	28 (50.9%)	40 (63.5%)	4 (80.0%)	.23
COPD	1 (1.8%)	6 (9.5%)	3 (60.0%)	<.001
Diabetes	11 (20.0%)	13 (20.6%)	3 (60.0%)	.11
Cancer	18 (32.7%)	22 (34.9%)	0 (0.0%)	.28
Paraganglioma	8 (14.5%)	4 (6.3%)	0 (0.0%)	.25
Pheochromocytoma	3 (5.5%)	1 (1.6%)	0 (0.0%)	.46
Carcinoid	0 (0.0%)	0 (0.0%)	1 (20.0%)	.041
GIST	1 (1.8%)	0 (0.0%)	0 (0.0%)	.54
Past surgical history, No. (%)
Prior thyroid or parathyroidectomy	0 (0.0%)	6 (9.5%)	0 (0.0%)	.050
Carotid endarterectomy	1 (1.8%)	0 (0.0%)	2 (40.0%)	<.001
CABG or thoracic aorta procedure	2 (3.6%)	2 (3.2%)	0 (0.0%)	.91
Prior head and neck radiation	3 (5.6%)	0 (0.0%)	1 (20.0%)	.022
Family history, No. (%)
Pertinent family history				.098
Familial SDHC	1 (1.8%)	1 (1.6%)	0 (0.0%)
Familial SDHD	7 (12.7%)	2 (3.2%)	0 (0.0%)
GIST	1 (1.8%)	0 (0.0%)	0 (0.0%)
Paraganglioma	3 (5.5%)	0 (0.0%)	0 (0.0%)
None	31 (56.4%)	50 (79.4%)	3 (60.0%)
Initial evaluation
Initially evaluating specialty				0.002
Otolaryngology	31 (57.4%)	25 (39.7%)	5 (100.0%)
Vascular surgery	20 (37.0%)	13 (20.6%)	0 (0.0%)
Neurosurgery	1 (1.9%)	8 (12.7%)	0 (0.0%)
Endocrine surgery	0 (0.0%)	1 (1.6%)	0 (0.0%)
Medical service	2 (3.7%)	16 (25.4%)	0 (0.0%)
Year of evaluation				0.56
2000–2004	4 (66.7%)	2 (33.3%)	0 (0.0%)
2005–2009	14 (51.9%)	10 (37.0%)	3 (11.1%)
2010–2014	23 (56.1%)	17 (41.5%)	1 (2.4%)
2015–2019	21 (44.7%)	24 (51.1%)	2 (4.3%)

The five initially radiated tumors were evaluated by otolaryngologists. These patients had a higher rate of hypertension, cardiopulmonary obstructive disease, and diabetes (Table 1). Three of the 5 patients were deemed unfit for surgery, and two had tumors which extended into the skull base, deemed unresectable. One initially radiated CBT demonstrated growth 5.6 years following initial diagnosis, which was successfully treated with additional radiation.

When comparing initially observed (N=63) to resected CBT (N=55), patients with initially resected CBT were younger (51±18 vs 65±18 years; P<.001), male (51% vs 21%; P=.003), and Caucasian (96% vs 80%; P=.008; Table 1). Initially resected CBT were more frequently symptomatic (29% vs 11%; P=.005) and larger (mean diameter, 27±11mm vs 20±10mm, P<.001; mean length, 29±11mm vs 28±14mm; P=.57) than those initially observed (Table 2). Sixty-one (50%) patients underwent functional testing, with a 10% positivity rate, all of which were initially resected (N=6). Eleven (9%) patients had a family history of CBT related syndromes (i.e., Familial Succinate Dehydrogenase [SDH] D or C) and 27 (22%) underwent somatic genetic testing, of which 63% (N=17/27) were found to have pertinent mutations (Table 2). Notably, only two patients (6%) underwent genetic testing prior to 2010, after which approximately one quarter of patients were tested. Fifteen (24%) of initially observed patients had documented reasons for not opting for up front surgical intervention. Six patients were medically frail, 5 did not want an operation, 4 had other metastatic cancers, and 1 was non-operable. Kaplan Meier curves with the associated 95%CI are captured in Figure 3 with observed differences between groups (log rank P=.025).

Table 2.

Initial evaluation CBT factors by initial treatment groups

Factor	Initial Surgical Resection	Initial Observation	Initial Radiation Therapy	p-value
N	55	63	5
Initial Imaging features
Imaging technique, No. (%)				.70
Computed Tomography	1 (2.1%)	2 (3.5%)	0 (0.0%)
Magnetic resonance imaging	30 (63.8%)	28 (49.1%)	3 (60.0%)
Ultrasound	15 (31.9%)	20 (35.1%)	2 (40.0%)
Angiography	1 (2.1%)	6 (10.5%)	0 (0.0%)
Tumor laterality, No. (%)				.26
Left	23 (41.8%)	35 (56.5%)	2 (40.0%)
Right	32 (58.2%)	27 (43.5%)	3 (60.0%)
Diameter, left, mean (SD)	3.1 (1.2)	2.2 (1.0)	2.6 (0.8)	.022
Length, left, mean (SD)	3.0 (1.3)	2.4 (1.0)	2.8 (.)	.25
Diameter, right, mean (SD)	2.4 (1.0)	1.8 (0.9)	5.1 (1.0)	<.001
Length, right, mean (SD)	2.9 (0.9)	3.4 (1.8)	5.1 (1.4)	.10
Initial CBT features and assessment, No. (%)
Any attributable CBT symptoms*	16 (29.1%)	7 (11.1%)	3 (60.0%)	.005
Attributable CBT symptoms*
Pain	1 (1.8%)	4 (6.3%)	0 (0.0%)	.41
Syncope	3 (5.5%)	0 (0.0%)	1 (20.0%)	.024
Dysphagia	5 (9.1%)	1 (1.6%)	2 (40.0%)	.002
Dysphonia	3 (5.5%)	1 (1.6%)	2 (40.0%)	<.001
Hearing loss or tinnitus	2 (3.6%)	2 (3.2%)	2 (40.0%)	<.001
Hemodynamic instability	4 (7.4%)	0 (0.0%)	0 (0.0%)	.074
Baseline functional testing	35 (64.8%)	25 (39.7%)	1 (20.0%)	.010
Baseline functional testing type				.15
Catecholamines	10 (28.6%)	6 (24.0%)	0 (0.0%)
Catecholamines & metanephrines	6 (17.1%)	12 (48.0%)	1 (100.0%)
Metanephrines	18 (51.4%)	7 (28.0%)	0 (0.0%)
Unknown	1 (2.9%)	0 (0.0%)	0 (0.0%)
Baseline functional testing positive	6 (17.1%)	0 (0.0%)	0 (0.0%)	.084
Genetic evaluation				.69
SDHD mutation	10 (18.2%)	4 (6.3%)	0 (0.0%)
SDHC mutation	1 (1.8%)	1 (1.6%)	0 (0.0%)
Polymerase Epsilon Mutation	1 (1.8%)	0 (0.0%)	0 (0.0%)
Neurofibromatosis-1	0 (0.0%)	1 (1.6%)	0 (0.0%)
Tested, no mutation	4 (7.3%)	5 (7.9%)	0 (0.0%)
Not tested	39 (70.9%)	52 (82.5%)	5 (100.0%)

^*CBT can result in more than one symptom.

Figure 3.

Kaplan Meier Curves Comparing Survival Among Those Initially Observed and Resected

Upon evaluation of baseline patient and CBT factors in multivariable modeling, CBT resection was associated with a younger age (aOR, 0.95 [95%CI, 0.92–0.97]; P<.001), male sex (aOR, 4.82 [95%CI, 1.47–15.75]; P=.009), evaluation by vascular surgeons compared to otolaryngologist (aOR, 6.17 [95%CI, 2.04–18.63]; P=.001). However, there was no significant association between CBT resection and race (aOR Black vs White, 4.54 [95%CI, 0.91–22.64]; P=.065) or baseline CBT diameter (aOR, 0.99 [95%CI, 0.60–1.62]; P=.953).

Overall, median follow-up was 4.7 (IQR, 2.6–9.1) years. From initial diagnosis, 53 (43%) CBT had follow-up imaging prior to final surgical or radiologic interventions. The median duration of imaging follow-up prior to any intervention was 2.1 (IQR, 0.7–4.9) years. Over time, 15 (28%) CBT decreased, 19 (36%) were stable, and 19 (36%) increased in size (Figure 2A). The overall average diameter change was 1±5mm/year. The patterns of diameter change per size category over time are visualized in Figure 2B.

Figure 2.

Changes in carotid body tumor size overtime

Diameter changes at the final point of follow up are categorized into decreasing (purple), stable (orange), and increasing (blue). The Panel A histogram demonstrates 64% of tumors are decreasing or stable in size. Among tumors categorized as increasing, Panel B demonstrates the growth rate overtime which constitutes an average of 0.2+/− 0.7cm per year of growths.

A total of 9 (14%) initially observed CBT crossed over to undergo resection or receive radiation therapy and therefore were categorized into a different final treatment category. Eight initially observed CBT underwent resection for bilateral tumors (4 CBT), patient preference (2 CBT), growth (1 CBT), and following diagnosis of a metastatic sternal paraganglioma (1 CBT) (Figure 1B). The metastatic disease was discovered 6.8 years following initial diagnosis upon new onset of chest wall pain. The patient was treated with CBT surgical resection as well as local and sternal radiation therapy with no recurrence over 3.1 additional years of follow-up. One initially observed patient presented 2.6 years following diagnosis with rapid expansion of the CBT and was found to have hemorrhagic conversion. The patient was treated with external beam radiation without issue.

The final CBT treatments included 63 (51%) surgical resection, 54 (44%) observation, 6 (5%) radiation therapy (Figure 1B). Prior to resection, nine (14%) patients underwent preoperative CBT embolization, and three (5%) patients underwent CBT biopsies of which two were equivocal and one reported malignancy, which was recategorized as benign on final pathology. Additional operative details are available in Table 3. Overall, 22% of carotids underwent surgical repair during CBT resection with no differences (N=11/55 [20.0%] vs N=3/8 [37.5%], P=.27) among those initially resected (primary repair N= 4 [7.3%], patch N=2 [3.6%], interposition graft N=5 [9.1%]) or those that crossed over into the final resection group (primary repair N= 2 [25.0%], patch N=1 [12.5%], interposition graft N=1 [12.5%]).

Table 3.

Outcomes for initially and crossover surgical resection groups

Factor	All Final Surgical Resections	Initial Surgical Resection	Crossover to Final Surgical Resection	p-value
N	63	55	8
Pre- and intraoperative factors
Time to resection, days, median (IQR)	48.0 (20, 89.0)	37.0 (18.5, 80.0)	203.0 (60.0, 232.0)	.002
Operating service				.67
ENT	40 (67.8%)	35 (66.0%)	5 (83.3%)
Vascular	17 (28.8%)	2 (3.8%)	0 (0.0%)
Neurosurgery	2 (3.4%)	16 (30.2%)	1 (16.7%)
Preoperative CBT embolization	9 (16.1%)	9 (17.6%)	0 (0.0%)	.31
Intraoperative neuromonitoring	21 (37.5%)	18 (35.3%)	3 (60.0%)	.28
Intraoperative EEG monitoring	14 (25.0%)	13 (25.5%)	1 (20.0%)	.79
Estimated blood loss, mL, median (IQR)	220.0 (50.0, 300.0)	210.0 (50.0, 300.0)	300.0 (25.0, 400.0)	.90
Operative duration, minutes, median (IQR)	225.0 (161.0, 292.0)	222.0 (161.0, 292.0)	272.0 (143.0, 300.0)	.76
External Carotid Artery Ligation	10 (15.9%)	10 (18.2%)	1 (12.5%)	.69
Any carotid repair	14 (22.2%)	11 (20.0%)	3 (37.5%)	.27
Postoperative outcomes
Any in-hospital postoperative complication*	19 (30.2%)	17 (30.9%)	2 (25.0%)	.73
Stroke	1 (2.0%)	0 (0.0%)	1 (16.7%)	.007
Respiratory distress**	3 (4.8%)	2 (3.6%)	1 (12.5%)	.27
Hemodynamic instability	3 (6.1%)	3 (7.0%)	0 (0.0%)	.50
Facial weakness	6 (9.5%)	6 (10.9%)	0 (0.0%)	.33
Vocal cord abnormalities	3 (4.8%)	3 (5.5%)	0 (0.0%)	.50
Voice changes	6 (9.5%)	6 (10.9%)	0 (0.0%)	.33
Tongue dysfunction	6 (9.5%)	6 (10.9%)	0 (0.0%)	.33
Dysphagia	4 (6.3%)	4 (7.3%)	0 (0.0%)	.43
Horner’s syndrome	3 (4.8%)	3 (5.5%)	0 (0.0%)	.50
Postoperative hospital length of stay, median (IQR)	2.0 (1.0, 3.0)	2.0 (1.0, 3.0)	2.0 (1.0, 4.0)	.92
CBT pathology and long-term CBT outcomes
Surgical pathology
Benign paraganglioma	51 (89.5%)	46 (90.2%)	5 (83.3%)
Malignant paraganglioma	5 (8.8%)	4 (7.8%)	1 (16.7%)	.73
Lymph node metastasis	4 (7.4%)	4 (8.3%)	0 (0.0%)	.46
Postoperative local radiation therapy of malignant CBT	2 (66.7%)	2 (100.0%)	0 (0.0%)	.083
Postoperative local recurrence***	3 (5.4%)	3 (5.9%)	0 (0.0%)	.58

^*Carotid body resections may result in more than one postoperative complication. Complications are limited only to those diagnosed during the index postoperative hospital admission.

^**Respiratory distress includes pneumonia, transfer to intensive care unit for respiratory monitoring, and reintubation. All 3 CBT resections resulted in significant recurrent laryngeal nerve injury which was attributable to the respiratory distress.

^***Of CBT with local recurrence, 2 had benign and 1 malignant final surgical pathology.

Overall, 19 (30%) CBT resections resulted in a postoperative complication diagnosed during the index hospital admission, which did not differ among initially resected (N=17/55, 30.9%) or initially observed (N=2/8, 25.0%; P=.73) CBT. CBT resections resulting in complications had a larger median diameter (25mm [IQR, 20–40] vs 20mm [IQR, 13–28mm]), (P=.020) and among those with preoperative CBT related symptoms (preoperative symptoms, N=7/16 [43.8%] vs no preoperative symptoms, N=9/47 [19.2%]; P=.051) although the latter failed to reach significance. However, complications did not significantly differ by preoperative embolization use (CBT embolization, N=4 [44.4%] vs no embolization N=15 [29.4%]; P=.371). A total of 35 postoperative complications occurred, including respiratory distress, and cranial neuropathies which again did not significantly vary by initial resection or observation with crossover to final resection (Table 3). Notably, no cranial nerve related complications were observed in the cohort of patients which were initially observed and 16 occurred in those initially resected (P=.077). However, a single 82-year-old male who was initially observed and crossed over into the final resection cohort experienced a postoperative stroke (P=.007). The patient crossed over into the delayed surgical intervention group (223 days following diagnosis) secondary to the patient’s indecision surrounding an operative treatment plan. The CBT was 3cm and Shamblin II both at initial diagnosis and at the time of resection. He received 7500U of heparin, the internal carotid was clamped, an intimal disruption was noted and repaired. He awoke with contralateral upper extremity weakness and was found to have corresponding ischemia in the middle cerebral artery region.

On final pathology, only 5 (8.8%) CBT were malignant, which included 3 CBT in patients with known somatic mutations (Polymerase Epsilon [N=1], Succinate Dehydrogenase-D gene [N=2]), 1 CBT resected for functional activity, and 1 CBT for known metastatic disease for which genetic or functional testing was not performed. Three CBT locally recurred, only 1 of which had malignant final pathology, 2 had a Succinate Dehydrogenase-D mutations, and all were treated non-operatively.

DISCUSSION

In our twenty-year, contemporary evaluation of CBT treatments by vascular, otolaryngologic, and neurologic surgeons as well as medical providers in a large healthcare system including both community and academic hospitals, nearly half were primarily observed while half underwent immediate surgical resection. Overall, 10% of patients tested had biochemically active CBT, 63% of those tested had a somatic mutation, and 8% of resected CBT were malignant. Sixty percent of the malignant CBT were associated with a somatic mutation and 20% were biochemically active. Among observed CBT with an average of five years of follow-up, the CBT size was stable with a mean diameter change of 1±5mm per year and none became biochemically active. Of the patients who underwent final CBT resection, nearly 30% had a postoperative complication and 5% recurred. Although classic teaching has been to resect CBT, our data allows review of outcomes among a variety of practice patterns allowing for the conclusion that primary observation of CBT with imaging and symptom monitoring may be considered as a safer alternative to immediate resection, which demonstrates a high rate of complications and ongoing risk of recurrence.

Prior CBT investigation focused on quantifying and describing complications following surgical resection. Numerous studies report 20–50% of patients suffer from postoperative adverse events,^{4, 16–18} which were associated with tumors located near the skull base, larger tumors encasing the carotid artery, advanced Shamblin classification, and need for concomitant lymph node resections.^{4, 19} In fact, a recent meta-analysis of 4,743 CBT resections in 4,418 patients uncovered one in four patients experienced a cranial nerve injury and 3.5% a postoperative stroke.⁶ The in-hospital postoperative complications in our study mirrored those reported previously, including mainly cranial nerve complications, ranging from temporary hemodynamic instability to dysphagia and Horner’s syndrome. We observed that larger and symptomatic CBT more frequently resulted in in-hospital postoperative complication; however, we were unable to ubiquitously quantify the Shamblin class. No in-hospital cranial nerve complications were identified among those patients who were initially observed. Notably, only one stroke occurred in our cohort. The 82-year-old man’s CBT was not particularly high risk in relation to its size or Shamblin classification. Further, although they were initially observed, their CBT did not increase in size or complexity during the 223 day wait period. Therefore, while this single event resulted in a statistically significant difference in the rate of stroke between those initially observed and resected, the act of waiting seems unlikely to have contributed to this patient’s postoperative outcome. In prior work, multiple tools have been investigated to minimize postoperative complications.^{20, 21} Preoperative CBT embolization has been investigated with disparate findings, resulting in case-specific utilization dictated by surgeon preference. Paralleling other rare diseases, the use of a multidisciplinary team, consisting of otolaryngologists and vascular surgeons, has found an unparalleled low rate of complications with shorter operative times.²² Independent of surgical tools and operative team used to minimize complications, we noted 3 patients (5%) who underwent technically successful CBT resection without complication went on to develop CBT recurrence. Therefore, consideration of both perioperative complications and our observation that CBT resection may not result in cure must inform the treatment decision.

In the aforementioned meta-analysis, the vast majority of patients presented with a neck mass and, like in our cohort, were otherwise asymptomatic.⁶ However, in contrast to the existing literature describing and evaluating strategies to minimize postoperative complications, little data exists on the natural history of a diagnosed, asymptomatic CBT. Recent work in the otolaryngology literature has explored primary observation of other cranial paragangliomas. Prasad et al., found that the majority of tympanojugular paragangliomas remained stable in size with over 10% demonstrating tumor regression.¹⁰ Furthermore, Carlson et al. demonstrated that among 12 patients with glomus jugulare tumors, over half remained stable in size.¹² Among the minority of glomus jugulare tumors demonstrating radiologic growth, the median growth rate was only 0.8mm per year overall and was even lower among older aged patients and tumors with larger volumes.¹⁵ CBT characteristics and practice patterns varied across provider specialties allowing for categorization of a variety of treatment plans. Patients referred for initial radiation therapy were done so exclusively by otolaryngologists among those deemed not fit for surgery or who had inoperable tumors. However, when available, the reasoning for initial observation was most frequently due to comorbid condition but represented solely patient preference for one in three. In multivariable regression, initial resection was associated with younger age, male sex, and evaluation by a vascular surgeon but not CBT diameter potentially demonstrating both provider and patient preferences for treatment. Our results mirror that of other head and neck paragangliomas with an extremely slow annual growth rate ranging from 1 to 2 mm per year.^{11, 14} Notably, other perceived reasons to initially resect CBT include concern for biochemical and malignant transformation or development of symptoms. Among all published findings and our cohort, no observed CBT were found to become biochemically active. Among CBT resected after an initial period of observation, the postoperative complication rates were equivalent to those who underwent immediate resection. The single initially observed patient who developed metastatic disease was successfully treated with local CBT resection as well as local and sternal radiation therapy without further complication or recurrence noted.

Despite the safety observed in our cohort study for primary observation of CBT, there are key patient and tumor characteristics which warrant immediate resection including malignancy and tumor bioactivity. All patients with newly diagnosed CBT should be screened for both local and biochemical symptoms and activity, characterized with non-invasive imaging studies, tested for serum or urine catecholamine and metanephrine excess, and evaluated for known somatic gene mutation testing which has become increasingly available in the modern treatment of patients. Notably, CBT biopsy in our data was not accurate in the evaluation of malignant CBT potential and in review of the literature caries a risk of bleeding.²³ Metheetrairut et al even found a statistically significant increase in vascular injury rate of resected CBT in those that had been previously biopsied.²⁴ We therefore recommend against CBT biopsy. Following initial evaluation, we recommend that newly diagnosed CBT could be considered primarily observed with annual non-invasive imaging with few exceptions. In our cohort, 60% of malignant CBT were associated with a somatic mutation and 20% were biochemically active. Due to this increased risk of malignancy, initial resection may be considered among patients with somatic gene mutations. Furthermore, catecholamine release and potentially associated cardiac and endocrine sequelae mandate biochemical testing for observed patients and testing-guided resection. Finally, patient and provider preference and comfort with non-operative management must be considered.

Our study has several limitations. First, although our CBT cohort is the first published work to explore CBT from diagnosis and investigate the natural history of tumors as well as non-operative CBT management, data were collected retrospectively and are limited to those available in the health record. Initially resected CBT were more common in younger patients and larger and therefore the average growth rates are more heavily influenced by those older in age. Ideally, we would perform a randomized control trial with an adequate sample size to investigate outcomes of interest in which patients are assigned to immediate resection versus non-operative management. Such an endeavor, however, would prove to be very challenging due to the rare nature of these tumors. Second, due to the inconsistent use of Shamblin classification in formal radiology reads as well as inability to access early images to evaluate ourselves, we were unable to include Shamblin classification as a variable of interest in this study which limits our understanding of CBT complexity. Third, although our data was abstracted from a large healthcare system including a wide breadth of surgical and medical providers in both community and academic hospitals, the enactment area is limited to Pennsylvania and the surrounding states limiting our sample size and therefore our ability to investigate secondary outcomes, differences among subgroups, and the feasibility of multivariable analysis. As CBT are rare and more prominent among those with a family history of such tumors, our observed correlation between somatic mutations and malignancy may lack applicability to a more diverse geographic area. Patients with unknown somatic mutations more common in other geographic regions may develop CBT that exhibit a different natural history and therefore additional work is required. Further, due the long duration of the study only in-patient complications were quantified.

In conclusion, patients with newly diagnosed CBT require biochemical functionality testing and known somatic mutation assessment. In the absence of these findings, our data suggest providers and patients may safely consider primary observation of CBT with annual imaging and symptom monitoring. Further research is needed to investigate observation as safe alternative to immediate resection, which demonstrates a high rate of vascular and cranial nerve related complications and an ongoing risk of recurrence.