Surgical management of carotid body tumors: a 15-year single institution experience employing an interdisciplinary approach Jennifer L. Dixon, MD, Marvin D. Atkins, MD, William T. Bohannon, MD, Clifford J. Buckley, MD, and Terry C. Lairmore, MD
Cervical paragangliomas are rare neoplasms that arise from extraadrenal paraganglia in close association with the cranial nerves and extracranial arterial system of the head and neck, and therefore surgical extirpation can be challenging. A retrospective study was conducted of all patients undergoing surgical excision of a cervical paraganglioma between 2000 and 2015. The demographic characteristics, clinical features, surgical approach, and outcomes were reviewed. A total of 20 cervical paragangliomas were excised in 17 patients. There were 14 female and 3 male patients with a mean age of 56.6 ± 17.0 at the time of operation. Twelve patients had unilateral tumors and 5 patients had bilateral tumors. Familial involvement was confirmed by history or direct genetic analysis in 8 (47%) of the 17 patients. There were no malignant paragangliomas, and only 3 patients had tumors that were determined to be functional. Tumor size ranged from 1.3 to 6.0 cm. Two patients required combined arterial resection as part of complete excision of the tumor. There were no permanent operative cranial nerve injuries, no recurrences, minimal morbidity, and no mortality. In conclusion, optimal management of cervical paragangliomas should include a thorough preoperative evaluation, accurate definition of the surgical anatomy, and exclusion of synchronous paragangliomas. A combined therapeutic approach by a multidisciplinary team including surgeons and interventional radiologists provides safe and effective management of cervical paragangliomas with very low morbidity and excellent outcomes.
C
arotid body tumors (CBTs) are rare neoplasms that arise near the carotid bifurcation within glomus cells derived from the embryonic neural crest. CBTs comprise approximately 65% of head and neck paragangliomas. Most paragangliomas (75%) are sporadic, but a subset (25%) are associated with hereditary paraganglioma syndrome. Cervical paragangliomas arise from the sympathetic ganglia in the head and neck, and similar tumors may arise from the vagus nerve ganglia (glomus vagale) (1–3). The majority of sporadic tumors are asymptomatic and initially found by palpation during physical exam, or more commonly as incidental findings on imaging studies (4, 5). Symptomatic patients present with pain, dysphagia, or autonomic dysfunction (1, 4, 6). Cervical paragangliomas are usually benign and biochemically silent, but functional and malignant tumors can occur in a small subset of patients. Sporadic benign tumors typi-
16
cally present between the ages of 40 and 70 years, whereas malignant tumors present at younger ages (20–40 years) (7). Hereditary paragangliomas result from mutations in the genes for succinate dehydrogenase (SDHD, SDHA, SDHC, SDHB). Patients with hereditary paraganglioma syndrome often undergo routine surveillance and, therefore, tumors can be detected at an earlier stage. Most cervical paragangliomas are slow growing, but left untreated they will eventually result in a progressive enlarging cervical mass with direct involvement and dysfunction of cranial nerves. Complete surgical removal is the treatment of choice for these tumors whenever technically achievable. Excision of CBTs can be technically challenging owing to their proximity to the cranial nerves and the extracranial arterial system, as well as the associated complex anatomy in the head and neck (Figure 1). In 1971, Shamblin introduced a classification system for these tumors based on size and extent of local involvement (8). This study reviews the outcomes of a standardized multidisciplinary approach to the treatment of patients with cervical paraganglioma at our institution, in conjunction with a review of previous publications on this topic. METHODS After approval by the institutional review board, all patients undergoing treatment for cervical paraganglioma from 2000 to 2015 were identified using a search for the associated ICD-9 diagnosis and CPT procedure codes. Demographic, biochemical, radiographic, and clinicopathologic information was collected by retrospective chart review; this information included age, gender, family history, functionality of the tumor, genetic studies, surgical details (case duration, blood loss), preoperative angioembolization, postoperative outcomes, and operative complications. The Shamblin classification was assigned retrospectively according to data from the operative and pathology reports (8). The results were compiled and analyzed using descriptive statistics. From Baylor Scott & White Healthcare and Texas A&M University Health Science Center College of Medicine, Temple, Texas. Corresponding author: Terry C. Lairmore, MD, Department of Surgery, Baylor Scott & White Health, MS-01-730C, 2401 South 31st Street, Temple, TX 76508 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(1):16–20
a
b
Figure 1. Exposure of carotid body tumor.
All patients underwent a complete history and physical evaluation by the primary surgical team. A complete family history was obtained, and (in the current era) where appropriate, formal genetic counseling and direct genetic testing for mutations in the succinate dehydrogenase (SDH) subunit genes was performed. Patients with a preoperative diagnosis of paraganglioma underwent biochemical screening to evaluate for a functional tumor, including measurement of fractionated plasma metanephrines and/or excretion of urine catecholamines and metabolites. Although CBTs are infrequently associated with catecholamine hypersecretion, it is our practice to perform biochemical testing for all patients with this diagnosis. Routine screening identifies those patients with secretory tumors and allows for preoperative alpha blockade to minimize perioperative complications from episodic catecholamine excess. Patients with functional tumors were begun on phenoxybenzamine 10 mg orally in divided doses 7 to 10 days preoperatively to allow for normalization of blood pressure and volume expansion. The preoperative evaluation, diagnostic imaging tests, and invasive procedures for preoperative preparation were performed with a multidisciplinary team approach by members of the interventional radiology, vascular surgery, and endocrine surgery/ surgical oncology services. Appropriate preoperative imaging was performed to assess the size, extent, and anatomic relationships of the tumor. These studies included cross-sectional imaging with contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and/or angiography. Preoperative angioembolization was performed selectively in patients with a tumor that was large, close to critical vessels, or was believed to benefit from reduced size/vascular supply prior to resection (Figure 2). The selection of patients for preoperative transarterial catheter embolization was therefore based on surgical judgment, as well as the experience and expertise of the interventional radiologist. After appropriate preoperative evaluation and informed consent, patients were taken to the operating room for primary excision under general anesthesia. The surgical technique included precise anatomic dissection and vascular control prior to attempted tumor excision. The dissection to remove the CBT was carried out along the arterial subadventitial plane to allow for complete local tumor excision, as well as preservation of critical vascular structures. In one patient the internal carotid artery required transection. Postoperative care included close January 2016
pharmacologic control of systolic blood pressure and postoperative clinical neurologic evaluation. In patients requiring arterial reconstruction following CBT resection, we prefer an autogenous venous conduit if an end-to-end arterial anastomosis is not feasible. Medical therapy following end-to-end reconstruction or venous interposition grafting is typically antiplatelet therapy with aspirin alone for at least a year, depending on the patient’s other comorbidities. In the single patient who required arterial reconstruction with a polytetrafluoroethylene graft/hybrid stent, we elected to keep the patient on dual antiplatelet therapy indefinitely given the limited data on such reconstructions. Patients with a known diagnosis of hereditary paraganglioma should undergo lifelong annual biochemical and clinical screening. Annual biochemical testing for plasma and/or urinary catecholamines should begin at age 10 or 10 years before the earliest age of tumor development in the family. Periodic imaging with CT/MRI or 123I-metaiodobenzylguanidine is indicated for surveillance in patients with a known SDH mutation and in patients with the development of symptoms or if the fractionated metanephrines and/or catecholamines become elevated. After resection of a CBT, patients should continue to have lifelong biochemical and clinical surveillance. Although no clear consensus has been developed regarding when, how, and how often biochemical studies and imaging should be performed, testing should be individualized to the patient. RESULTS Seventeen patients were identified with either single or bilateral cervical paragangliomas, and a total of 20 tumors were excised. The female to male ratio was 4.7:1, with ages of 22 to 79 years (mean 56.6 ± 17.0) at the time of operation. The follow-up period for the study patients was 1 to 126 months (mean 56 ± 34 months). Twelve patients had unilateral tumors and 5 patients had bilateral tumors. Some patients with bilateral involvement underwent removal of the larger tumor first, a
b
Figure 2. Angiography of carotid body tumor.
Surgical management of carotid body tumors: a 15-year single institution experience employing an interdisciplinary approach
17
Table 1. Consecutive patients Patient
Age
Gender
Follow-up (months)
Arterial resection
Size Shamblin Familial Functional Preop (cm) class history tumor embolized
1
62
M
126
0
2.6
II
+
+
0
Stroke
2
75
F
115
+
5.0
III
+
0
+
Cerebral salt wasting
3
77
F
106
0
2.0
I
0
0
0
0
4
63
F
85
0
2.5
II
0
0
0
0
5
40
M
62
0
2.5
II
0
0
+
0
5*
40
M
57
0
1.7
I
0
0
+
0
6
59
F
71
0
3.7
II
0
0
+
0
6*
60
F
67
0
2.7
II
0
0
+
0
7
74
F
52
0
1.3
I
0
0
0
0
8
79
F
70
0
1.3
I
0
0
0
0
9
68
F
63
0
2.8
I
0
0
+
Preoperative vocal cord paralysis
10
67
F
57
0
2.3
II
0
0
0
Temporary dysphagia
11
54
F
49
0
3.0
I
0
0
0
0
12
66
F
49
0
3.0
II
+
0
+
0
13
42
M
42
0
1.6
I
+
0
0
0
14
29
F
15
0
2.4
I
+
0
0
0
14*
29
F
11
0
1.5
I
+
0
0
0
15
22
F
11
0
3.8
II
0
+
+
Temporary dysphagia
16
73
F
5
+
6.0
III
+
0
+
Vagus sacrificed due to tumor involvement
17
52
F
1
0
3.5
I
0
+
+
0
Complication/nerve injury
*Duplicate numbers indicate bilateral resections in the same patient.
with a smaller asymptomatic contralateral lesion either followed expectantly or with a planned staged resection depending on individual patient and physician preference. A cervical mass was present preoperatively in 8 (47%) patients. Familial involvement was confirmed by history or direct genetic analysis in 8 (47%) of the 17 patients. There were no malignant paragangliomas in this series, and only three tumors were determined to be functional by preoperative biochemical testing. The excised tumors ranged from 1.3 to 6.0 cm (mean 2.76 ± 1.17 cm) in size. Most of the tumors were Shamblin class I and II, as depicted in Table 1 (4, 5, 9–12). Two patients had recognized preoperative vocal cord paralysis due to tumor involvement of the vagus nerve. There were no permanent operative nerve injuries. One nonfunctioning preoperative nerve was sacrificed at the time of tumor resection. Two patients had postoperative difficulty swallowing that was transient and resolved by the first clinical follow-up visit. Preoperative angiographic embolization was performed for 10 of 20 (50%) of the excised tumors. Two patients required a combined arterial resection as part of complete excision of the tumor. For one patient, an arterial resection was performed and a primary end-to-end anastomosis was achieved for reconstruction. A second patient had reconstruction with a polytetrafluoroethylene hybrid vascular graft. No patients had tumor recurrence during the follow-up period, and there was no perioperative mortality. 18
DISCUSSION A complete preoperative evaluation should be performed in patients with a known or suspected cervical paraganglioma, including a directed family history and genetic testing when appropriate. Hereditary paraganglioma syndromes occur in approximately 25% of cases, and the SDH enzyme complex gene mutation has been identified as the cause of familial types (13–15). Patients with hereditary paraganglioma syndrome have a greater incidence of bilateral tumors and develop tumors at a younger age than those with sporadic tumors. Functional tumors are detected by preoperative biochemical screening, including measurement of plasma metanephrines and urine catecholamines. Patients with functional tumors should be prepared preoperatively with alpha-adrenergic receptor blockade to prevent dangerous blood pressure elevations intraoperatively. Hormonally active cervical paragangliomas are reported to be very infrequent (1%–3%) (16). Only three patients had functional tumors in our series, and most patients were asymptomatic, presenting with either a painless neck mass or the detection of a cervical tumor on imaging obtained for other reasons. Six patients in the current series had familial involvement based on genetic testing or history. Early excision of cervical paragangliomas is recommended to prevent the development of larger, more locally advanced tumors (Shamblin class III), which are associated with a higher incidence of operative nerve injury as well as poorer outcomes (17).
Baylor University Medical Center Proceedings
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Published nerve injury rates range from 11% to 50% (1, 4, 5, 18, 19) and increase with higher Shamblin class (1, 7). Operative injuries (transient Year Authors (ref) or permanent) of the vagus nerve, hy2005 Luna-Ortiz et al (5) poglossal nerve, sympathetic chain, 2006 Antonitsis et al (9) or marginal mandibular branch of 2008 Makeieff et al (10) the facial nerve have been associated 2009 Grotemeyer et al (11) with operative treatment of CBTs (5, 2010 Kruger et al (12) 18), especially in larger tumors with close proximity to critical structures 2011 O’Neill et al (4) requiring a more complex procedure for removal. All but two patients in 2015 Dixon et al our series had Shamblin class I or II *Transient injuries. tumors, and the incidence of transient or permanent cranial nerve injuries in our series is low. Patients with bilateral tumors should undergo staged resections with surgical removal of one side at a time to obviate the risk of synchronous bilateral cranial nerve injury with attendant significant morbidity. Unfortunately, vascular and especially cranial nerve injuries occur relatively frequently in patients requiring excision of large or bilateral CBTs. The baroreflex failure syndrome can occur after the bilateral excision of CBTs (20). Preoperative embolization of large, vascular tumors can facilitate surgical treatment. This typically includes embolization of the ascending pharyngeal branch of the external carotid, allowing for up to 75% reduction in tumor blood flow. The optimal timing is generally 1 to 2 days prior to surgical excision (4, 21). At our institution, embolization is performed by neurointerventional radiologists. They also assess the internal carotid artery if there is potential need for ligation. Prior to embolization, a pretest is performed by means of a soft balloon in the internal carotid artery on that side. The patient is assessed for any neurologic changes, and the balloon is deflated if necessary. If no changes are detected, the blood pressure is dropped to simulate mild hypotension (systolic blood pressure 90–100) and verify that the patient still has no symptoms. If the patient passes the test, then the patient will tolerate internal carotid artery ligation without reconstruction. Most modern series of CBTs reserve preoperative embolization for Shamblin III tumors. In the present series, all Shamblin III and some of the Shamblin I and II tumors underwent preoperative embolization. More liberal use of preoperative embolization during CBT resection for Shamblin I and II tumors has resulted in decreased operative blood loss in individual surgeon experience within our group. Although there is a risk of stroke or other complications with preoperative angiography and embolization, we did not experience that in our small series. That risk, albeit small, has limited preoperative embolization for Shamblin I and II tumors at other institutions. In addition to perioperative complications of nerve injury and bleeding, excision of CBTs is associated with a risk of perioperative stroke. Table 2 shows complication rates in many historical series. Arterial manipulation results in a very small January 2016
Table 2. Historical series Patients F:M (n) ratio Malignant Bilateral Functional
Family history
Nerve injury
53
31:1
0
3 (5%)
–
0
23 (49%)
13
1.6:1
0
1 (8%)
0
–
7 (54%)
52
2.1:1
1 (2%)
3 (6%)
3 (6%)
4 (8%)
24 (42%)
36
1.8:1
0
6 (17%)
–
–
23 (64%)
39
2:1
7 (18%)
–
–
11 (28%)
13 (27%)
29
1:1
1 (3%)
6 (21%)
–
17
4.7:1
0
5 (29%)
3 (18%)
4 (14%) *8 (25%) 8 (47%)
*1 (7%)
associated stroke risk, which approaches 0% in many experienced hands but can be as high as 11% in some reports (5). In our series, one patient had a perioperative stroke (5.9%). This patient (patient 1) did not require carotid occlusion during the operation. He was initially neurologically intact postoperatively and was discharged home on postoperative day 1. However, he returned on postoperative day 3 with complaints of weakness and slurred speech. He was found to have an infarct of the ipsilateral brainstem on MRI. He subsequently required physical therapy and rehabilitation for convalescence. Paragangliomas may be initially detected during ultrasound or Doppler ultrasound of the neck; however CT and MRI are more sensitive for accurate tumor measurement (22). The typical radiologic findings include a hypervascular, hypoechoic tumor with splaying of the carotid bifurcation. 123I-metaiodobenzylguanidine scintigraphy images paraganglioma tumor tissue based on the selective uptake of precursors for catecholamine synthesis, but is most useful in detecting occult paragangliomas or extraadrenal tumors in unusual anatomic sites and is therefore infrequently utilized (16). More widespread and frequent use of sensitive imaging modalities enhances early tumor detection. This may explain the decreasing rates of radical carotid artery resection and the declining rate of nerve injury (3). Higher Shamblin class tumors are associated with greater blood loss, longer operative times, higher incidence of nerve injury, and the need for vascular sacrifice and reconstruction (14, 23). Complete operative excision remains the treatment of choice for CBTs when it can be performed safely. This requires a surgical team with extensive experience and expertise in the management of these complex tumors. Some patients have been treated with radiation therapy for these tumors; however, the current recommendation is for surgical excision alone, unless significant structural involvement prohibits safe surgical exploration (2, 18). 1.
2.
Del Guercio L, Narese D, Ferrara D, Butrico L, Padricelli A, Porcellini M. Carotid and vagal body paragangliomas. Transl Med UniSa 2013;6(6):11– 15. Kataria T, Bisht SS, Mitra S, Abhishek A, Ptharaju S, Chakarvarty D. Synchronous malignant vagal paraganglioma with contralateral carotid body paraganglioma treated by radiation therapy. Rare Tumors 2010;2(2):e21.
Surgical management of carotid body tumors: a 15-year single institution experience employing an interdisciplinary approach
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4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
20
Kollert M, Minovi AA, Draf W, Bockmuhl U. Cervical paragangliomas— tumor control and long-term functional results after surgery. Skull Base 2006;16(4):185–191. O’Neill S, O’Donnell M, Harkin D, Loughrey M, Lee B, Blair P. A 22-year northern Irish experience of carotid body tumours. Ulster Med J 2011;80(3):133–140. Luna-Ortiz K, Rascon-Ortiz M, Villavicencio-Valencia V, GranadosGarcia M, Herrera-Gomez A. Carotid body tumors: review of a 20-year experience. Oral Oncol 2005;41(1):56–61. Beigi AA, Ashtari F, Salari M, Norouzi R. Convulsive syncope as presenting symptom of carotid body tumors: case series. J Res Med Sci 2013;18(2):164–166. Obholzer RJ, Hornigold R, Connor S, Gleeson MJ. Classification and management of cervical paragangliomas. Ann R Coll Surg Engl 2011;93(8):596–602. Shamblin WR, Remine WH, Sheps SG, Harrison EG. Carotid body tumor (chemodectoma). Clinicopathologic analysis of ninety cases. Am J Surg 1971;122(6):732–739. Antonitsis P, Saratzis N, Velissaris I, Lazaridis I, Melas N, Ginis G, Giavroglou C, Kiskinis D. Management of cervical paragangliomas: review of a 15-year experience. Langenbecks Arch Surg 2006;391(4): 396–402. Makeieff M, Raingeard I, Alric P, Bonafe A, Guerrier B, Marty-Ane Ch. Surgical management of carotid body tumors. Ann Surg Oncol 2008;15(8):2180–2186. Grotemeyer D, Loghmanieh SM, Pourhassan S, Sagban TA, Iskandar F, Reinecke P, Sandmann W. Dignity of carotid body tumors. Review of the literature and clinical experiences. Chirurg 2009;80(9):854–863. Kruger AJ, Walker PJ, Foster WJ, Jenkins JS, Boyne NS, Jenkins J. Important observations made managing carotid body tumors during a 25-year experience. J Vasc Surg 2010;52(6):1518–1523. Schiavi F, Dematte S, Cecchini ME, Taschin E, Bobisse S, Del Piano A, Donner D, Barbareschi M, Manera V, Zovato S, Erlic Z, Savvoukidis T, Barollo S, Grego F, Trabalzini F, Amista P, Grandi C, Branz F, Marroni F, Neumann HP, Opocher G. The endemic paraganglioma syndrome
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type I: origin, spread, and clinical expression. J Clin Endocrinol Metab 2012;97(4):E637–E641. Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F, Jouanno E, Jeunemaitre X, Benit P, Tzagoloff A, Rustin P, Bertherat J, Favier J, Gimenez-Roqueplo AP. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010;19(15):3011–3020. Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000;26(3):268–270. Offergeld C, Brase C, Yaremchuk S, Mader I, Rische HC, Glasker S, Schmid KW, Wiech T, Preuss SF, Suarez C, Kopec T, Patocs A, Wohllk N, Malekpour M, Boedeker CC, Neumann HP. Head and neck paragangliomas: clinical and molecular genetic classification. Clinics (Sao Paulo) 2012;67(Supp 1):19–28. Lim JY, Kim J, Kim SH, Lee S, Lim YC, Kim JW, Choi EC. Surgical treatment of carotid body paragangliomas: outcomes and complications according to Shamblin classification. Clin Exp Otorhinolaryg 2010;3(2):91–95. Neskey DM, Hatoum G, Modh R, Civantos F, Telischi FF, Angeli SI, Weed D, Sargi Z. Outcomes after surgical resection of head and neck paragangliomas: a review of 61 patients. Skull Base 2011;21(3):171–176. Davidovic LB, Djukic VB, Vasic DM, Sindjelic RP, Duvnjak SN. Diagnosis and treatment of carotid body paraganglioma: 21 year experience at a clinical center of Serbia. World J Surg Oncol 2005;3(1):10. DeToma G, Nicolanti V, Plocco M, Cavallaro G, Letizia C, Piccirillo G, Cavallaro A. Baroreflex failure syndrome after bilateral excision of carotid body tumors: an underestimated problem. J Vasc Surg 2000;31:806–810. White JB, Link MJ, Cloft HJ. Endovascular embolization of paragangliomas: a safe adjuvant to treatment. J Vac Interv Neurol 2008;1(2):37–41. Dematte S, DiSarra D, Schiavi F, Casadei A, Opocher G. Role of ultrasound and color Doppler imaging in detection of carotid paragangliomas. J Ultrasound 2012;15(3):158–163. Luna-Ortiz K, Rascon-Ortiz M, Villavicencio-Valencia V, Herrera-Gomez A. Does Shamblin’s classification predict postoperative morbidity in carotid body tumors? A proposal to modify Shamblin’s classification. Eur Arch Otorhinolaryngol 2006;263(2):171–175.
Baylor University Medical Center Proceedings
Volume 29, Number 1
Cervical paragangliomas are rare neoplasms that arise from extraadrenal paraganglia in close association with the cranial nerves and extracranial arterial system of the head and neck, and therefore surgical extirpation can be challenging. A retrospective study was conducted of all patients undergoing surgical excision of a cervical paraganglioma between 2000 and 2015. The demographic characteristics, clinical features, surgical approach, and outcomes were reviewed. A total of 20 cervical paragangliomas were excised in 17 patients. There were 14 female and 3 male patients with a mean age of 56.6 ± 17.0 at the time of operation. Twelve patients had unilateral tumors and 5 patients had bilateral tumors. Familial involvement was confirmed by history or direct genetic analysis in 8 (47%) of the 17 patients. There were no malignant paragangliomas, and only 3 patients had tumors that were determined to be functional. Tumor size ranged from 1.3 to 6.0 cm. Two patients required combined arterial resection as part of complete excision of the tumor. There were no permanent operative cranial nerve injuries, no recurrences, minimal morbidity, and no mortality. In conclusion, optimal management of cervical paragangliomas should include a thorough preoperative evaluation, accurate definition of the surgical anatomy, and exclusion of synchronous paragangliomas. A combined therapeutic approach by a multidisciplinary team including surgeons and interventional radiologists provides safe and effective management of cervical paragangliomas with very low morbidity and excellent outcomes.
C
arotid body tumors (CBTs) are rare neoplasms that arise near the carotid bifurcation within glomus cells derived from the embryonic neural crest. CBTs comprise approximately 65% of head and neck paragangliomas. Most paragangliomas (75%) are sporadic, but a subset (25%) are associated with hereditary paraganglioma syndrome. Cervical paragangliomas arise from the sympathetic ganglia in the head and neck, and similar tumors may arise from the vagus nerve ganglia (glomus vagale) (1–3). The majority of sporadic tumors are asymptomatic and initially found by palpation during physical exam, or more commonly as incidental findings on imaging studies (4, 5). Symptomatic patients present with pain, dysphagia, or autonomic dysfunction (1, 4, 6). Cervical paragangliomas are usually benign and biochemically silent, but functional and malignant tumors can occur in a small subset of patients. Sporadic benign tumors typi-
16
cally present between the ages of 40 and 70 years, whereas malignant tumors present at younger ages (20–40 years) (7). Hereditary paragangliomas result from mutations in the genes for succinate dehydrogenase (SDHD, SDHA, SDHC, SDHB). Patients with hereditary paraganglioma syndrome often undergo routine surveillance and, therefore, tumors can be detected at an earlier stage. Most cervical paragangliomas are slow growing, but left untreated they will eventually result in a progressive enlarging cervical mass with direct involvement and dysfunction of cranial nerves. Complete surgical removal is the treatment of choice for these tumors whenever technically achievable. Excision of CBTs can be technically challenging owing to their proximity to the cranial nerves and the extracranial arterial system, as well as the associated complex anatomy in the head and neck (Figure 1). In 1971, Shamblin introduced a classification system for these tumors based on size and extent of local involvement (8). This study reviews the outcomes of a standardized multidisciplinary approach to the treatment of patients with cervical paraganglioma at our institution, in conjunction with a review of previous publications on this topic. METHODS After approval by the institutional review board, all patients undergoing treatment for cervical paraganglioma from 2000 to 2015 were identified using a search for the associated ICD-9 diagnosis and CPT procedure codes. Demographic, biochemical, radiographic, and clinicopathologic information was collected by retrospective chart review; this information included age, gender, family history, functionality of the tumor, genetic studies, surgical details (case duration, blood loss), preoperative angioembolization, postoperative outcomes, and operative complications. The Shamblin classification was assigned retrospectively according to data from the operative and pathology reports (8). The results were compiled and analyzed using descriptive statistics. From Baylor Scott & White Healthcare and Texas A&M University Health Science Center College of Medicine, Temple, Texas. Corresponding author: Terry C. Lairmore, MD, Department of Surgery, Baylor Scott & White Health, MS-01-730C, 2401 South 31st Street, Temple, TX 76508 (e-mail: [email protected]). Proc (Bayl Univ Med Cent) 2016;29(1):16–20
a
b
Figure 1. Exposure of carotid body tumor.
All patients underwent a complete history and physical evaluation by the primary surgical team. A complete family history was obtained, and (in the current era) where appropriate, formal genetic counseling and direct genetic testing for mutations in the succinate dehydrogenase (SDH) subunit genes was performed. Patients with a preoperative diagnosis of paraganglioma underwent biochemical screening to evaluate for a functional tumor, including measurement of fractionated plasma metanephrines and/or excretion of urine catecholamines and metabolites. Although CBTs are infrequently associated with catecholamine hypersecretion, it is our practice to perform biochemical testing for all patients with this diagnosis. Routine screening identifies those patients with secretory tumors and allows for preoperative alpha blockade to minimize perioperative complications from episodic catecholamine excess. Patients with functional tumors were begun on phenoxybenzamine 10 mg orally in divided doses 7 to 10 days preoperatively to allow for normalization of blood pressure and volume expansion. The preoperative evaluation, diagnostic imaging tests, and invasive procedures for preoperative preparation were performed with a multidisciplinary team approach by members of the interventional radiology, vascular surgery, and endocrine surgery/ surgical oncology services. Appropriate preoperative imaging was performed to assess the size, extent, and anatomic relationships of the tumor. These studies included cross-sectional imaging with contrast-enhanced computed tomography (CT), magnetic resonance imaging (MRI), and/or angiography. Preoperative angioembolization was performed selectively in patients with a tumor that was large, close to critical vessels, or was believed to benefit from reduced size/vascular supply prior to resection (Figure 2). The selection of patients for preoperative transarterial catheter embolization was therefore based on surgical judgment, as well as the experience and expertise of the interventional radiologist. After appropriate preoperative evaluation and informed consent, patients were taken to the operating room for primary excision under general anesthesia. The surgical technique included precise anatomic dissection and vascular control prior to attempted tumor excision. The dissection to remove the CBT was carried out along the arterial subadventitial plane to allow for complete local tumor excision, as well as preservation of critical vascular structures. In one patient the internal carotid artery required transection. Postoperative care included close January 2016
pharmacologic control of systolic blood pressure and postoperative clinical neurologic evaluation. In patients requiring arterial reconstruction following CBT resection, we prefer an autogenous venous conduit if an end-to-end arterial anastomosis is not feasible. Medical therapy following end-to-end reconstruction or venous interposition grafting is typically antiplatelet therapy with aspirin alone for at least a year, depending on the patient’s other comorbidities. In the single patient who required arterial reconstruction with a polytetrafluoroethylene graft/hybrid stent, we elected to keep the patient on dual antiplatelet therapy indefinitely given the limited data on such reconstructions. Patients with a known diagnosis of hereditary paraganglioma should undergo lifelong annual biochemical and clinical screening. Annual biochemical testing for plasma and/or urinary catecholamines should begin at age 10 or 10 years before the earliest age of tumor development in the family. Periodic imaging with CT/MRI or 123I-metaiodobenzylguanidine is indicated for surveillance in patients with a known SDH mutation and in patients with the development of symptoms or if the fractionated metanephrines and/or catecholamines become elevated. After resection of a CBT, patients should continue to have lifelong biochemical and clinical surveillance. Although no clear consensus has been developed regarding when, how, and how often biochemical studies and imaging should be performed, testing should be individualized to the patient. RESULTS Seventeen patients were identified with either single or bilateral cervical paragangliomas, and a total of 20 tumors were excised. The female to male ratio was 4.7:1, with ages of 22 to 79 years (mean 56.6 ± 17.0) at the time of operation. The follow-up period for the study patients was 1 to 126 months (mean 56 ± 34 months). Twelve patients had unilateral tumors and 5 patients had bilateral tumors. Some patients with bilateral involvement underwent removal of the larger tumor first, a
b
Figure 2. Angiography of carotid body tumor.
Surgical management of carotid body tumors: a 15-year single institution experience employing an interdisciplinary approach
17
Table 1. Consecutive patients Patient
Age
Gender
Follow-up (months)
Arterial resection
Size Shamblin Familial Functional Preop (cm) class history tumor embolized
1
62
M
126
0
2.6
II
+
+
0
Stroke
2
75
F
115
+
5.0
III
+
0
+
Cerebral salt wasting
3
77
F
106
0
2.0
I
0
0
0
0
4
63
F
85
0
2.5
II
0
0
0
0
5
40
M
62
0
2.5
II
0
0
+
0
5*
40
M
57
0
1.7
I
0
0
+
0
6
59
F
71
0
3.7
II
0
0
+
0
6*
60
F
67
0
2.7
II
0
0
+
0
7
74
F
52
0
1.3
I
0
0
0
0
8
79
F
70
0
1.3
I
0
0
0
0
9
68
F
63
0
2.8
I
0
0
+
Preoperative vocal cord paralysis
10
67
F
57
0
2.3
II
0
0
0
Temporary dysphagia
11
54
F
49
0
3.0
I
0
0
0
0
12
66
F
49
0
3.0
II
+
0
+
0
13
42
M
42
0
1.6
I
+
0
0
0
14
29
F
15
0
2.4
I
+
0
0
0
14*
29
F
11
0
1.5
I
+
0
0
0
15
22
F
11
0
3.8
II
0
+
+
Temporary dysphagia
16
73
F
5
+
6.0
III
+
0
+
Vagus sacrificed due to tumor involvement
17
52
F
1
0
3.5
I
0
+
+
0
Complication/nerve injury
*Duplicate numbers indicate bilateral resections in the same patient.
with a smaller asymptomatic contralateral lesion either followed expectantly or with a planned staged resection depending on individual patient and physician preference. A cervical mass was present preoperatively in 8 (47%) patients. Familial involvement was confirmed by history or direct genetic analysis in 8 (47%) of the 17 patients. There were no malignant paragangliomas in this series, and only three tumors were determined to be functional by preoperative biochemical testing. The excised tumors ranged from 1.3 to 6.0 cm (mean 2.76 ± 1.17 cm) in size. Most of the tumors were Shamblin class I and II, as depicted in Table 1 (4, 5, 9–12). Two patients had recognized preoperative vocal cord paralysis due to tumor involvement of the vagus nerve. There were no permanent operative nerve injuries. One nonfunctioning preoperative nerve was sacrificed at the time of tumor resection. Two patients had postoperative difficulty swallowing that was transient and resolved by the first clinical follow-up visit. Preoperative angiographic embolization was performed for 10 of 20 (50%) of the excised tumors. Two patients required a combined arterial resection as part of complete excision of the tumor. For one patient, an arterial resection was performed and a primary end-to-end anastomosis was achieved for reconstruction. A second patient had reconstruction with a polytetrafluoroethylene hybrid vascular graft. No patients had tumor recurrence during the follow-up period, and there was no perioperative mortality. 18
DISCUSSION A complete preoperative evaluation should be performed in patients with a known or suspected cervical paraganglioma, including a directed family history and genetic testing when appropriate. Hereditary paraganglioma syndromes occur in approximately 25% of cases, and the SDH enzyme complex gene mutation has been identified as the cause of familial types (13–15). Patients with hereditary paraganglioma syndrome have a greater incidence of bilateral tumors and develop tumors at a younger age than those with sporadic tumors. Functional tumors are detected by preoperative biochemical screening, including measurement of plasma metanephrines and urine catecholamines. Patients with functional tumors should be prepared preoperatively with alpha-adrenergic receptor blockade to prevent dangerous blood pressure elevations intraoperatively. Hormonally active cervical paragangliomas are reported to be very infrequent (1%–3%) (16). Only three patients had functional tumors in our series, and most patients were asymptomatic, presenting with either a painless neck mass or the detection of a cervical tumor on imaging obtained for other reasons. Six patients in the current series had familial involvement based on genetic testing or history. Early excision of cervical paragangliomas is recommended to prevent the development of larger, more locally advanced tumors (Shamblin class III), which are associated with a higher incidence of operative nerve injury as well as poorer outcomes (17).
Baylor University Medical Center Proceedings
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Published nerve injury rates range from 11% to 50% (1, 4, 5, 18, 19) and increase with higher Shamblin class (1, 7). Operative injuries (transient Year Authors (ref) or permanent) of the vagus nerve, hy2005 Luna-Ortiz et al (5) poglossal nerve, sympathetic chain, 2006 Antonitsis et al (9) or marginal mandibular branch of 2008 Makeieff et al (10) the facial nerve have been associated 2009 Grotemeyer et al (11) with operative treatment of CBTs (5, 2010 Kruger et al (12) 18), especially in larger tumors with close proximity to critical structures 2011 O’Neill et al (4) requiring a more complex procedure for removal. All but two patients in 2015 Dixon et al our series had Shamblin class I or II *Transient injuries. tumors, and the incidence of transient or permanent cranial nerve injuries in our series is low. Patients with bilateral tumors should undergo staged resections with surgical removal of one side at a time to obviate the risk of synchronous bilateral cranial nerve injury with attendant significant morbidity. Unfortunately, vascular and especially cranial nerve injuries occur relatively frequently in patients requiring excision of large or bilateral CBTs. The baroreflex failure syndrome can occur after the bilateral excision of CBTs (20). Preoperative embolization of large, vascular tumors can facilitate surgical treatment. This typically includes embolization of the ascending pharyngeal branch of the external carotid, allowing for up to 75% reduction in tumor blood flow. The optimal timing is generally 1 to 2 days prior to surgical excision (4, 21). At our institution, embolization is performed by neurointerventional radiologists. They also assess the internal carotid artery if there is potential need for ligation. Prior to embolization, a pretest is performed by means of a soft balloon in the internal carotid artery on that side. The patient is assessed for any neurologic changes, and the balloon is deflated if necessary. If no changes are detected, the blood pressure is dropped to simulate mild hypotension (systolic blood pressure 90–100) and verify that the patient still has no symptoms. If the patient passes the test, then the patient will tolerate internal carotid artery ligation without reconstruction. Most modern series of CBTs reserve preoperative embolization for Shamblin III tumors. In the present series, all Shamblin III and some of the Shamblin I and II tumors underwent preoperative embolization. More liberal use of preoperative embolization during CBT resection for Shamblin I and II tumors has resulted in decreased operative blood loss in individual surgeon experience within our group. Although there is a risk of stroke or other complications with preoperative angiography and embolization, we did not experience that in our small series. That risk, albeit small, has limited preoperative embolization for Shamblin I and II tumors at other institutions. In addition to perioperative complications of nerve injury and bleeding, excision of CBTs is associated with a risk of perioperative stroke. Table 2 shows complication rates in many historical series. Arterial manipulation results in a very small January 2016
Table 2. Historical series Patients F:M (n) ratio Malignant Bilateral Functional
Family history
Nerve injury
53
31:1
0
3 (5%)
–
0
23 (49%)
13
1.6:1
0
1 (8%)
0
–
7 (54%)
52
2.1:1
1 (2%)
3 (6%)
3 (6%)
4 (8%)
24 (42%)
36
1.8:1
0
6 (17%)
–
–
23 (64%)
39
2:1
7 (18%)
–
–
11 (28%)
13 (27%)
29
1:1
1 (3%)
6 (21%)
–
17
4.7:1
0
5 (29%)
3 (18%)
4 (14%) *8 (25%) 8 (47%)
*1 (7%)
associated stroke risk, which approaches 0% in many experienced hands but can be as high as 11% in some reports (5). In our series, one patient had a perioperative stroke (5.9%). This patient (patient 1) did not require carotid occlusion during the operation. He was initially neurologically intact postoperatively and was discharged home on postoperative day 1. However, he returned on postoperative day 3 with complaints of weakness and slurred speech. He was found to have an infarct of the ipsilateral brainstem on MRI. He subsequently required physical therapy and rehabilitation for convalescence. Paragangliomas may be initially detected during ultrasound or Doppler ultrasound of the neck; however CT and MRI are more sensitive for accurate tumor measurement (22). The typical radiologic findings include a hypervascular, hypoechoic tumor with splaying of the carotid bifurcation. 123I-metaiodobenzylguanidine scintigraphy images paraganglioma tumor tissue based on the selective uptake of precursors for catecholamine synthesis, but is most useful in detecting occult paragangliomas or extraadrenal tumors in unusual anatomic sites and is therefore infrequently utilized (16). More widespread and frequent use of sensitive imaging modalities enhances early tumor detection. This may explain the decreasing rates of radical carotid artery resection and the declining rate of nerve injury (3). Higher Shamblin class tumors are associated with greater blood loss, longer operative times, higher incidence of nerve injury, and the need for vascular sacrifice and reconstruction (14, 23). Complete operative excision remains the treatment of choice for CBTs when it can be performed safely. This requires a surgical team with extensive experience and expertise in the management of these complex tumors. Some patients have been treated with radiation therapy for these tumors; however, the current recommendation is for surgical excision alone, unless significant structural involvement prohibits safe surgical exploration (2, 18). 1.
2.
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