Single-cell transcriptome analysis reveals tumoral microenvironment heterogenicity and hypervascularization in human carotid body tumor.

Carotid body tumor (CBT) is a rare neck tumor located at the adventitia of the common carotid artery bifurcation. The prominent pathological features of CBT are high vascularization and abnormal proliferation. However, single-cell transcriptome analysis of the microenvironment composition and molecular complexity in CBT has yet to be performed. In this study, we performed single-cell RNA sequencing (scRNA-seq) analysis on human CBT to define the cells that contribute to hypervascularization and chronic hyperplasia. Unbiased clustering analysis of transcriptional profiles identified 16 distinct cell populations including endothelial cells (ECs), smooth muscle cells (SMCs), neuron cells, macrophage cells, neutrophil cells, and T cells. Within the ECs population, we defined subsets with angiogenic capacity plus clear signs of later endothelial progenitor cells (EPCs) to normal ECs. Two populations of macrophages were detectable in CBT, macrophage1 showed enrichment in hypoxia-inducible factor-1 (HIF-1) and as well as an early EPCs cell-like population expressing CD14 and vascular endothelial growth factor. In addition to HIF-1-related transcriptional protein expression, macrophages1 also display a neovasculogenesis-promoting phenotype. SMCs included three populations showing platelet-derived growth factor receptor beta and vimentin expression, indicative of a cancer-associated fibroblast phenotype. Finally, we identified three types of neuronal cells, including chief cells and sustentacular cells, and elucidated their distinct roles in the pathogenesis of CBT and abnormal proliferation of tumors. Overall, our study provided the first comprehensive characterization of the transcriptional landscape of CBT at scRNA-seq profiles, providing novel insights into the mechanisms underlying its formation.

Challenges of Surgical Resection of Carotid Body Tumors - Multiple Feeding Arteries and Preoperative Embolization.

BACKGROUND: Carotid body tumor is a hypervascular tumor with multiple feeding arteries and unique orientation at the carotid bifurcation. Although resection is a radical therapy for this tumor, complete resection is challenging. MATERIALS AND METHODS: Articles reporting carotid body tumor treatment and surgical resection were reviewed including case-control series and review articles. RESULTS: Selected reports were reviewed and discussed focusing on choice of treatment, surgical difficulties and preoperative embolization of feeding arteries. CONCLUSION: Multiple feeding arteries and adhesion of the tumor to the carotid arterial wall are causes of difficulties in carotid body tumor resection. The effectiveness of preoperative embolization remains controversial due to the varied situations in performing surgical resection among the institutions. However, perfect embolization and resection immediately after embolization reduce blood loss and operative time of surgery for carotid body tumor.

Descending musculospinal branch of the ascending pharyngeal artery as a feeder of carotid body tumors: Angio-architecture and embryological consideration.

INTRODUCTION: Although the ascending pharyngeal artery (APhA) is known as a main feeder of carotid body tumors (CBTs), its detailed architecture and embryological consideration have not been described. The objective of this study was to describe the architecture of a descending feeder of the APhA and to consider its origin embryologically through a review of our CBT embolizations. METHODS: We retrospectively analyzed data from patients with CBTs who underwent transarterial embolization or angiographic examination-only between July 2010 and February 2017. The arterial supply of the tumors, the number of feeder pedicles, the mean tumor size, embolization materials, complication of embolization, and extent of tumor removal were assessed. The embryological origin of feeding artery was considered based on the literature. RESULTS: Eighteen patients with 20 CBTs underwent preoperative embolization or angiographic examination. The number of feeder pedicles was significantly related to the size of the CBT (P = 0.0002). The main feeding artery was the descending branch of APhA, which was hypertrophied and tortuous (18/20, 90%). Embryologically, this artery originated from the musculospinal branch and is termed the "descending musculospinal branch". CONCLUSION: The main feeder of the CBTs was the "descending musculospinal branch" of the APhA and needs special consideration such as dangerous anastomosis for embolization.

Carotid Body Tumor Resection: Just as Safe without Preoperative Embolization.

BACKGROUND: Carotid body tumors (CBTs) are rare entities for which surgical resection remains the gold standard. Given their hypervascularity, preoperative embolization is often used; however, controversy exists over whether a benefit is associated. Proponents of embolization argue that it minimizes blood loss and complications. Critics argue that cost and stroke outweigh benefits. This study aimed to investigate the impact of embolization on outcomes following CBT resection. METHODS: Patients undergoing CBT resection were identified using the Healthcare Cost and Utilization Project State Inpatient Database for 5 states between 2006 and 2013. Patients were divided into 2 groups: carotid body tumor resection alone (CBTR) and carotid body tumor resection with preoperative arterial embolization (CBETR). Descriptive statistics were calculated using arithmetic means with standard deviations for continuous variables and proportions for categorical variables. Patients were propensity score matched on the basis of sex, age, race, insurance, and comorbidity prior to analysis. Risk-adjusted odds of mortality, stroke, nerve injury, blood loss, and length of stay (LOS) were calculated using mixed-effects regression models with fixed effects for age, race, sex, and comorbidities. RESULTS: A total of 547 patients were identified. Of these, 472 patients underwent CBTR and 75 underwent CBETR. Mean age was 54.7 ± 16 years. Mean number of days between embolization and resection was 0.65 ± 0.72 days (range 0-3). When compared with CBTR, there were no significant differences in mortality for CBETR (1.35% vs. 0%, P = 0.316), cranial nerve injury (2.7% vs. 0%, P = 0.48), and blood loss (2.7% vs. 6.8%, P = 0.245). Following risk adjustment, CBETR increased the odds of prolonged LOS (odds ratio 5.3, 95% confidence interval 2.1-13.3). CONCLUSIONS: CBT resection is a relatively rare procedure. The utility of preoperative tumor embolization has been questioned. This study demonstrates no benefit of preoperative tumor embolization.

[Percutaneous Phil™-Embolization for Preoperative Therapy of Carotid Body Paragangliomas]. / Perkutane Phil™-Embolisation zur präoperativen Therapie von Karotis-Paragangliomen.

Introduction: Paragangliomas are rare tumors representing a therapeutic challenge. In particular, the surgical removal may lead to life-threatening bleeding. The preoperative percutaneous embolization is an alternative that allows a high closure rate of tumor-feeding vessels in a short intervention time and thus significantly reduces intraoperative bleeding probability. Complete tumor resection is facilitated thereby. The use of a new non-adhesive liquid embolic agent is presented here. Methods: A 50-year old patient presented with 4 cm large paraganglioma of the carotid body (Shamblin II). A percutaneous embolization with 7 ml PHIL™ (injectable precipitating hydrophobic liquid) was performed preoperatively. 24 h later the complete surgical resection of the tumor was performed. Results: A good distribution of the liquid embolic agent could be achieved over the entire tumor. Intraoperative resection of the tumor was much easier and faster due to low bleeding tendency over the entire surface of the tumor. Total blood loss was less than 50 ml. All adjacent nerve and arterial structures could be spared. Postoperative nerve function was normal and the patient was discharged on the 4th postoperative day. Conclusion: The combination of percutaneous embolization and surgical resection provides a safe combination in the treatment of advanced carotid body paragangliomas. The use of a novel liquid embolic agent may possibly further optimize the therapy.

A simple technique to achieve bloodless excision of carotid body tumors.

We describe a technique for Shamblin II-III carotid body tumor (CBT) resection to reduce bleeding and neurologic complications during surgery. The technique was based on the fact that CBTs are supplied almost exclusively from the external carotid artery. Therefore, we carefully isolated the origin of the external carotid artery and its distal branches outside the tumor and temporarily clamped all of these vessels after heparin administration. This allowed a safe and bloodless resection as the tumor was dissected from the internal carotid artery in the usual subadventitial plane. The internal carotid artery was never clamped, and respect of peripheral nerves was warranted in the clean and bloodless field. From 2007 to 2010, we treated 11 patients with a CBT: six had a Shamblin II and five had a Shamblin III lesion. Neither perioperative neurologic events nor recurrences occurred after a mean follow-up of 42 months.

Double osteotomy of mandibula in the treatment of carotid body tumors with skull base extension.

We report two patients with a carotid body paraganglioma that extended to the skull base, a position that is surgically inaccessible by means of a traditional lateral cervical approach. In both patients we were able to remove the lesion by performing a double mandibular osteotomy. Both patients underwent preoperative embolization to reduce the mass. In our experience, this approach has allowed a safe radical excision of exceptionally high lesions with only minor permanent nerve damage. In our opinion this advantage definitely outweighs the consequences of the increased invasiveness of this technique.

Perioperative approach in the surgical management of carotid body tumors.

BACKGROUND: Now, surgical resection still remains the gold standard for the treatment of carotid body tumors (CBTs). Although advances in surgical techniques and the introduction of sensitive imaging modalities have significantly reduced mortality, the incidence of perioperative neurovascular complications, especially cranial nerve deficit and intraoperative hemorrhage, remains considerable. To solve these problems, preoperative embolization has been suggested; the reported benefits of preoperative embolization performed <48 hours before surgery include a reduction in tumor size, decreased blood loss, and improved visualization, theoretically reducing neurologic morbidity by lessening the risk of stroke and damage to cranial nerves. The purpose of this study was to review our experience in the surgical management of CBTs with preoperative embolization and evaluate the outcomes and complications according to the Shamblin classification. METHODS: Thirty-two patients who had been diagnosed with and surgically treated for CBTs were enrolled from January 2005 till July 2010. All perioperative scans were evaluated by computed tomography angiography. We reviewed patient demographics, radiographic findings, and surgical outcomes collected from medical records. RESULTS: Thirty-two patients underwent surgical excision without mortality. Angiography with selective preoperative tumor embolization was performed on 21 patients. The median blood loss, operation time, and hospital stay for these patients were significantly reduced compared with those without embolization. There were no recurrences or delayed complications at the median follow-up of 20 months. CONCLUSION: Embolization as an adjunctive tool was beneficial for CBT surgery outcomes. Embolization should only be undertaken in those vessels that can be subselectively catheterized and determined not to allow free reflux of contrast medium into the internal carotid artery. Tumor embolization was performed on patients with Cook detachable coils, which are highly effective for supply artery closure if properly selected, and complications can be minimized by proper selection and positioning of the coil. Operation within 48 hours after embolization is recommended to minimize revascularization edema or a local inflammatory response.

Results of combined preoperative direct percutaneous embolization and surgical excision in treatment of carotid body tumors.

BACKGROUND: Carotid body tumors are infrequent neoplasms in daily practice. Diagnostic difficulties exist because of their slow growth and asymptomatic progress. The surgical treatment is complicated and difficult due to their proximity to vascular and neural structures. In this study we present the results of 12 patients operated for carotid body tumor that underwent preoperative percutaneous direct embolization. PATIENTS AND METHODS: The data of 12 patients, diagnosed with carotid body tumor and surgically treated at our department between 2000 and 2010, was retrospectively analyzed. Duplex ultrasound, computerized tomography and selective carotid angiography were the applied diagnostic tools. Two days before the planned surgery all patients underwent percutaneous direct embolization to achieve devascularization of the tumor. Afterwards, surgical excision of the mass under general anesthesia was performed in all cases. RESULTS: Five tumors were classified as Shamblin type I (41.7%), and the others were type II (58.3%). All masses were removed sub-adventitially and no vascular reconstruction was necessary. There was no mortality and no permanent neural damage. Malfunction of the tongue was observed in only one case, which recovered completely in one month. There was one recurrence detected by Duplex ultrasound and angiography during the follow up period. CONCLUSIONS: Surgical excision is mandatory to be performed as soon as diagnosed in carotid body tumors. Preoperative direct percutaneous embolization of the mass helps to devascurize the tumor, enabling an optimal surgical procedure. The outcomes of such a combined intervention are excellent and neurovascular structure preservation decreases complication and morbidity rates.

Early side effects after embolization of a carotid body tumor using Onyx.

The case of a 20-year-old woman with a carotid body tumor of Shamblin class III is reported. Ten hours after preoperative direct intralesional embolization with 20 mL Onyx (ethylene-vinyl alcohol copolymer; Micro Therapeutics, Irvine, Calif), the patient showed symptoms of Horner syndrome and deficits of the hypoglossal and glossopharyngeal nerves. Intraoperative examination 12 hours after Onyx embolization revealed a massive swelling of the hypoglossal and glossopharyngeal nerves. The patient's tongue motility and glossopharyngeal function improved after surgery, but Horner syndrome was still present. Owing to the delayed occurrence of these adverse effects, the optimal time of surgical intervention after Onyx embolization should be discussed and perhaps expedited.

[Direct percutaneous embolization of a carotid body tumor with Onyx]. / Perkutane Onyx(R)-Embolisation zur Therapie von Glomus-caroticum-Tumoren.

Carotid body tumors are highly vascularized lesions that require successful preoperative embolization to achieve favorable clinical results in terms of morbidity and complete tumor resection. The procedure of percutaneous embolization was performed using ethylene-vinyl alcohol copolymer (Onyx) in addition to balloon-catheter protection to prevent particle displacement into the internal carotid artery. The procedure resulted in nearly complete tumor embolization and facilitated the uneventful complete surgical resection. Percutaneous angiographic embolization of carotid body tumors in the head and neck was found to be safe and effective. This technique is likely to result in improved surgical outcomes and tumor resectability.

[Experience of surgical treatment of carotid body tumor after preoperative embolization of feeding vessels].

OBJECTIVE: To evaluate the effect of preoperative embolization of the feeding vessels of carotid body tumor in the treatment thereof. METHODS: 33 patients with carotid body tumors not less than 3 cm in diameter were examined by color Doppler ultrasound. Polyvinyl alcohol particle 250-1000 microm in diameter were suspended in meglumine diatrizoate or Ultravist and then injected via microcatheter into the feeding vessels until detainment or reflux was seen. Operation was performed 1 day later on 23 patients and 4 days later on 10 patients. External carotid artery to internal carotid artery bypass was performed on 1 case, anastomosis of common carotid to internal carotid artery with auto-saphenous vein interposition on 3 cases, and repair of internal carotid artery on 1 case. RESULTS: One-stage resection was completed on all tumors. One case suffered contralateral hemiplegia two times in the operative day, on the next day the contralateral lower limb could move, but the patient could not speak clearly and his tongue was not in right position, after 3 months he was completely recovered and MRI illustrated cranial infarction. CONCLUSION: An important adjunct in treating large carotid body tumor, preoperative embolization makes the surgical exploration proceed much smoother, blood loss become less, and morbidity lower.

Direct percutaneous embolization of a carotid body tumor with Onyx.

Carotid body tumors (CBTs) are rare highly vascular lesions that frequently require preoperative embolization to minimize surgical morbidity secondary to blood loss. Embolization has typically been performed via a transarterial route. However, this frequently results in incomplete devascularization of the tumor due to the complex angioarchitecture of the feeding arteries. Direct intralesional embolization has been used to gain easier accesses to the tumor vasculature and thus increase the likelihood of complete embolization. Cyanoacrylate glue has been the most commonly used embolic agent. The authors present a case of CBT that underwent direct intralesional embolization using Onyx (ev3; ethylene vinyl alcohol copolymer). To their knowledge, there have been no previous reports of direct percutaneous embolization of a CBT with this agent.

Intraoperative monitoring of intraarterial paraganglioma embolization by indocyaningreen fluorescence angiography.

Preoperative arterial embolization (AE) of paraganglioma (PG) is widely used to diminish intraoperative blood loss. Thereby conditions for a resection of the tumor shall be improved and risks for facial, vagal or hypoglossus nerve injuries are reduced. The vascularization of jugular and tympanic PGs is particularly complex due to collaterals with the vertebral and internal carotid arteries. Thus AE is often not complete and intraoperative blood loss may still be considerable. The postinterventional perfusion is of interest for the surgeon. We evaluated the arterial perfusion after AE using indocyaningreen (ICG) angiography. Six patients with PG, two carotid PGs, two jugular PGs, one vagal PG and one tympanic PG underwent surgery 1 day after AE. After tumor was exposed, ICG was intravenously applied followed by fluorescence angiography. Residual perfusion was assessed on the video clip and the perfusion index was automatically calculated by the IC-CALC software. This index was compared with the radiologist's assessment of arteriographic control after AE. Two of the six patients showed only marginal residual perfusion. These were patients with carotid PGs. The patient with the vagal PG showed 20%, the patients with jugular PGs 80 and 60% and the patient with the tympanic PG had 70% residual blood flow. The preoperative AE is rarely complete in PGs of the petrous bone. Intraoperative fluorescence angiography is a reliable procedure to evaluate the efficiency of preoperative embolization and can help the surgeon to estimate intraoperative bleeding favouring risks.

Successful devascularization of carotid body tumors by covered stent placement in the external carotid artery.

Management of highly vascular carotid body tumors can involve pre-operative percutaneous embolization before definitive surgical resection. This step reduces tumor size, reduces operative blood loss, and makes for a less hazardous dissection with the goal of reducing morbidity and mortality. The effectiveness of a recently described technique of interrupting vascular supply via covered stent placement in the external carotid artery is further described in a series of three recent cases. This technique may be useful for large tumors with a primary blood supply from the external carotid since it avoids the intracranial embolic risk of coils used for this purpose.