Multimodality approach for advanced-stage juvenile nasopharyngeal angiofibromas

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1 ORIGINAL ARTICLE Multimodality approach for advanced-stage juvenile nasopharyngeal angiofibromas Fernando Lopez Alvarez, MD, PhD,* Vanessa Suarez, MD, PhD, Carlos Suarez, MD, PhD, Jose L. Llorente, MD, PhD Department of Otorhinolaryngology, Instituto Universitario de Oncología del Principado de Asturias, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain. Accepted 30 November 2011 Published online 2 February 2012 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Juvenile nasopharyngeal angiofibromas (JNAs) with significant skull base involvement and intracranial extension are challenging tumors. We evaluated our experience in the treatment of extensive JNAs through resection followed by radiosurgery. Methods. From 1999 to 2007, 10 advanced JNAs (Andrews grade IV) were treated by primary surgical resection followed by gamma knife radiosurgery of residual tumor. Tumor control and treatment morbidity were evaluated. Results. Six months after radiosurgery and annually thereafter, an imaging study was done that revealed decrement in tumor size in 3 patients and no change in 7 patients, after a 3-year minimum followup. Clinically, patients are asymptomatic. Conclusion. An efficient strategy in the management of extensive JNAs is the use of a multimodality approach, in which surgical resection is followed by the treatment with radiosurgery in critical locations. These therapeutic schemes are safe and offer long-term tumor control. VC 2012 Wiley Periodicals, Inc. Head Neck 35: , 2013 KEY WORDS: juvenile nasopharyngeal angiofibroma, advancedstage, radiosurgery, treatment, multimodality approach INTRODUCTION Juvenile nasopharyngeal angiofibromas (JNAs) are uncommon and highly vascular tumors affecting mostly adolescent male patients. JNAs arise at the posterolateral wall of the nasal cavity close to the sphenopalatine foramen and, although histologically benign, they may develop an aggressive growth pattern which can lead to significant skull base involvement and intracranial extension. JNAs have been managed according to various protocols, including surgery and radiotherapy. Of them, complete surgical excision remains the primary treatment for these patients. 1 The cure with early-stage disease (Andrews grade I III) is approximately 100% using noninvasive surgical approaches with reduced morbidity. 2 However, at the time of diagnosis, skull base extension occurs in 10% to 36% of cases and intracranial extension is observed in 20% of cases. In these extended JNAs (Andrews grade IV), management is still a surgical challenge and external approaches play an important role. These procedures provide the ability to resect large tumors but the risks and the morbidity associated with these procedures are relatively high and may still leave residual disease. In view of the proximity of the tumor to critical locations such as the optic apparatus or the cavernous sinus, radiosurgery has been used to treat residual tumor after incomplete surgical excision. *Corresponding author: F. Lopez Alvarez, C/Marcos Pe~na Royo, 20 4 A, Oviedo Asturias (Espa~na). flopez_1981@yahoo.es We present our experience with 10 extended JNAs treated by primary surgical resection through an open approach followed by radiosurgery of residual tumor. The purpose of this report was to describe the potential adjunctive role of radiosurgery for the management of extensive JNAs. MATERIALS AND METHODS The surgical medical charts of the otorhinolaryngology department of our hospital, from 1999 to 2007, were reviewed to collect data regarding the clinical data of patients diagnosed and treated for JNAs. The methodology was a retrospective, nonrandomized medical chart review. Written informed consent was obtained from each patient. Epidemiological and clinical data, surgical reports, preoperative and postoperative images, details concerning complications, and follow-up information were retrieved and analyzed. Preoperatively, all patients were evaluated with high-resolution contrast-enhanced CT, MRI, or both. CT scans showed the erosion of the skull base and MRI scans were useful to demonstrate the intracranial and intraorbital extension. Skull base involvement was defined as radiographic evidence of bone erosion of the skull base excluding the pterygoid plates, anterior wall of sphenoid sinus, orbital walls, and maxillary sinus walls. This series represents our experience with 10 patients with residual JNAs treated by stereotactic gamma knife radiosurgery. This subgroup of patients was extracted from a larger population of 51 consecutive patients diagnosed with JNAs who had been treated during the same period. The excluded patients had JNAs that were treated HEAD & NECK DOI /HED FEBRUARY

2 LoPEZ ALVAREZ ET AL. through radical surgical resection and they had no residual tumor or recurrence after a mean postoperative follow-up of 85 months. The present review encompasses 10 male patients harboring an extensive tumor mass involving the intracranial compartment that could be classified as stage IV tumors based on the Andrews classification, 3 whereas the 41 other patients harbored focal tumors (Andrews grade I III). All patients had undergone prior surgery and then stereotactic gamma knife radiosurgery was used as an adjunctive therapy for the management of patients after incomplete resection when the residual tumor volume did not exceed a 5 cm 3 and if the clearance between the JNAs and optic apparatus was at least 5 mm. Tumors were treated using a multi-isocentric protocol. The gamma knife radiosurgery parameters and dose selection varied with the tumor size and its relationship to the visual pathways. Maximum doses to the tumor ranged from 18 to 30 Gray (Gy), and the mean center dose was 22 Gy. The dose that was delivered at the tumor margin ranged from 14 to 20 Gy, corresponding to the 45% to 50% isodose. The maximal allowable dose to the optic apparatus, the brain stem, the third and fifth cranial nerves, the temporal lobe, and pituitary was less than 8 Gy. The 8-mm collimator was the most frequently used to treat all tumors. The follow-up consisted of periodic clinic visits to our clinic. During these visits, the patients were asked about any suspicious symptoms and were examined using a nasal endoscope. A CT and/or MRI was performed annually on all patients for the first 5 years of follow-up. After that, radiographic studies were only performed if the patient developed new symptoms. Analysis of postgamma knife radiosurgery imaging was performed to determine if each tumor's volume had increased, decreased, or remained the same. Complete response after radiation therapy was defined as complete regression of the tumor on physical examination and on follow-up imaging studies. Enlargement was noted if the tumor increased in volume. A tumor was considered stable in size if there was no change in size. Patients with residual static or resolving abnormalities over repeated imaging were considered to be locally controlled. Duration of local control was calculated from the date of surgery. We performed a routine check of the thyroid and parathyroid function in all these patients. The average follow-up period was 8 years and the longest follow-up in this study was 15 years. RESULTS All patients were men and their mean age at the time of diagnosis was 16 years (range, years). The tumors were located on the right side in 4 patients (40%) and on the left side in 6 patients (60%). The mean interval between the first symptom and diagnosis was 10 months (range, 3 23 months). Nasal obstruction was the most common clinical presentation (80%) of the disease followed by epistaxis (50%). Data on 10 patients are presented in Table 1. All JNAs eroded the skull base and showed extension to the endocranium and the intradural space. Eight cases (80%) progressed through the infratemporal fossa and 4 cases (40%) to the orbital apex. JNAs were classified according to their location and growth pattern using the Andrews staging. All tumors were Andrews grade IV. Angiography was performed in all patients. The vessels feeding the tumors were identified as the external carotid system (internal maxillary artery, ascending pharyngeal artery, and middle meningeal artery) in 3 patients (30%), as the external and internal carotid systems in 3 patients (60%), and as the internal carotid system only in 1 patient (10%). Selective embolization 24 to 48 hours before surgery was performed in 7 cases (70%) with polyvinyl alcohol particles. In 1 case, embolization could not be performed due to the blood supply that originated exclusively from the internal carotid system, and in the remaining 2 cases, due to the existence of an arterio-arterial fistula. There were no complications after embolization. Surgery was the initial treatment in all patients, but complete tumor resection was not possible and residual tumor was noted in all cases after surgery. The surgical approach used in each case was typically chosen depending on the stage and extension of the tumor and personal experience of the surgeon. Because the high likelihood of producing significant morbidity and due to the fact that JNAs are usually benign lesions, tumor fragments located near the orbital apex, into the cavernous sinus, or attached to the TABLE 1. Juvenile nasopharyngeal angiofibroma. Clinical data. Cases Age, y Prior surgery Andrews stage Sites Surgery Case 1 14 PLN (2 times) IVa S, PPF, ITF, SB, END, DUR SA Case 2 18 IVa S, PPF, ITF, SB, END, DUR IFT-FT Case 3 16 IVa S, PPF, ITF, SB, O, END, DUR SP Case 4 13 PLN (3 times) IVa S, PPF, ITF, SB, O, END, DUR SP Case 5 16 IVa PPF, SB, O, END, DUR IFT-FT Case 6 18 C-L IVb S, PPF, SB, END, DUR SP Case 7 15 IVa PPF, ITF, SB, END, DUR AFT Case 8 17 EA (4 times) IVa S, PPF, ITF, SB, END, DUR SP Case 9 11 IVa PPF, ITF, SB, O, END, DUR AFT Case PLN IVa S, PPF, ITF, SB, END, DUR AFT Abbreviations: PLN, paralateronasal approach; S, sphenoid; PPF, pterygopalatine fossa; ITF, infratemporal fossa; SB, skull base; END, endocranium; DUR, intracranial intradural; SA, subcranial approach; IFT-FT, intratemporal approach with facial translocation; O, orbital apex; SP, subtemporal-preauricular approach; C L, Caldwell Luc approach; AFT, anterior facial translocation; EA, endoscopic approach. 210 HEAD & NECK DOI /HED FEBRUARY 2013

3 ADVANCED-STAGE JUVENILE NASOPHARYNGEAL ANGIOFIBROMAS Preoperative symptoms improved significantly in all patients, except for a decrease in visual acuity observed for 1 patient. Immediate and follow-up postoperative MRI studies revealed residual tumor in all cases near the cavernous sinus or in the vicinity of the internal carotid artery. The residual tumor was not eligible for a more aggressive attempt of resection after consideration of the risk of potential vascular or neurologic damage. The mean residual volume was 3.7 cm 3 (range, cm 3 ). Between 2 and 7 months after surgery, all patients were treated with gamma knife radiosurgery (Figure 1). Table 2 shows some characteristics of the radiation in each patient. Patients tolerated treatment without complications. So far, no abnormalities were detected in thyroid and parathyroid function. Follow-up MRI studies were performed annually and revealed marked decrement of the size of tumor in 3 patients and no change in 7 patients after a 3-year minimum follow-up. Clinically, patients are highly functional, asymptomatic, and without neurologic deficits (Table 2). FIGURE 1. (A) View of residual juvenile nasopharyngeal angiofibroma (JNA) involving the cavernous sinus region after subtemporal-preauricular approach on CT scan, measuring approximately 3.0 cm 3. (B) Gadolinium-enhanced, T1-weighted MR images showing dose distribution for radiosurgery. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] internal carotid artery were not removed avoiding the mobilization of critical neurovascular structures. All patients underwent open surgical approaches. These approaches have been extensively detailed in other articles. We used the subtemporal-preauricular infratemporal approach in the resection of 4 JNAs (40%), modified anterior facial translocation in 3 cases (30%), infratemporal fossa approach with facial translocation in 2 cases (20%), and subcranial approach in 1 case (10%). DISCUSSION Most authors agree that surgery is the primary and exclusive treatment of JNAs when gross total resection can be achieved. 4,5 It has clearly been shown that the extent of initial surgery is crucial to prevent recurrences. However, surgery is sometimes challenging because of the bleeding tendency of the tumor and the extent to the skull base, orbit, and intracranial structures. Surgical excision has been considered an efficacious treatment option in the early stages (Andrews grade I III) of disease and the rate of radical cure in these stages is nearly 100%. These results can be achieved through a transoral or transfacial approaches which shares the need to make oral or facial incisions and the need to remove or divide bone to gain access to the tumor. However, advances in radiologic imaging, improvements of preoperative embolization, and the development of endoscopic techniques have contributed to improved surgical planning and tumor resection. For these reasons, the use of an endoscopic approach is undoubtedly a good option for management of JNAs and can be considered appropriate for early staged lesions (Andrews grade I IIIa). 5 Advanced-stage JNAs (stage IV) are still a surgical challenge and wide cranial base and intracranial extension TABLE 2. Juvenile nasopharyngeal angiofibroma, radiosurgery treatment, and outcomes. Case no. Location of residual tumor Size, cm 3 Radiosurgery (maximum dose) Months between surgery and GKS Follow-up, y Size after treatment, cm 3 Current status 1 CS (bilateral) 5 GKR (18 Gy; 50% isodose line) DS 2 ICA, CS 3.1 GKR (26 Gy; 50% isodose line) NC 3 CS (right) 1.8 GKR (24 Gy; 50% isodose line) DS 4 ICA, CS 3 GKR (20 Gy; 45% isodose line) NC 5 CS 4.5 GKR (30 Gy; 55% isodose line) NC 6 CS (bilateral) 5 GKR (18 Gy; 52% isodose line) NC 7 CS, SB 4.2 GKR (28 Gy; 50% isodose line) NC 8 ICA, CS 4.1 GKR (20 Gy; 52% isodose line) DS 9 CS 3.2 GKR (20 Gy; 50% isodose line) NC 10 ICA, CS 2.9 GKR (24 Gy; 55% isodose line) NC Abbreviations: CS, cavernous sinus region; GKR, gamma knife radiosurgery; Gy, Gray; DS, decrement of size; ICA, petrous internal carotid artery; NC, no change; SB, skull base. HEAD & NECK DOI /HED FEBRUARY

4 LoPEZ ALVAREZ ET AL. of JNAs may require extensive open approaches to try a tumor removal with acceptable morbidity. 4 The indications for endoscopic surgery in the management of JNAs have been expanded and even Andrews stage IIIb and IVa lesions may be successfully managed by expertise surgeons. However, an external or combined approach may be required when critical structures such as the internal carotid artery, cavernous sinus, or optic nerve are involved, as in our series. Tumors infiltrating the infratemporal fossa, the sphenoid sinus, the base of the pterygoid, the cavernous sinus, the foramen lacerum, and the anterior or middle fossa are the most vulnerable to incomplete excision and recurrence. The infratemporal approaches and the facial translocation approach offer an excellent exposure in tumors with a large degree of involvement of the nasopharyngeal region of the skull base, clivus, sphenoid, cavernous sinuses, the entire infratemporal fossa, and the orbital apex. Sometimes, these approaches may be combined with a craniofacial approach or an endoscopic approach. A craniofacial approach allows better management of the feeders that provide the blood supply directly from the cavernous portion of the internal carotid artery. Such procedures resulted in a 80% rate of radical cure. 2 Most of these procedures require facial incisions that carry the potential for unesthetic facial scarring and potential disturbance of bony facial development. To achieve a similar efficacy with acceptable complications, we advocate the anterior facial translocation by means of a midfacial degloving, which avoids facial scarring, and preauricular subtemporal-infratemporal approach for treatment of most large JNAs. Facial translocation is the method of choice in large volume tumors, especially when the posterior nasal space, sphenoid, orbit pterygopalatine, and infratemporal fossa are compromised. A disadvantage of this approach is the relatively poor access to the skull base behind the tumor and, although most intracranial lesions can be safely removed because the tumor grows with a pushing border that can be dissected from the dura relatively easily, the complete extirpation of these tumors may be difficult if bleeding is severe. In these cases, an ipsilateral hemicoronal incision is needed to access securely to the skull base. The preauricular subtemporal-infratemporal is used especially when the tumor has a limited anterior extension that nevertheless affects the infratemporal fossa toward the floor of the media fossa or the parasellar region. This approach also permits bilateral access to the nasopharynx and permits ligation of the internal maxillary artery early in the dissection, thus limiting intraoperative blood loss. We use this approach in removing a JNA when it is not too voluminous and affects the nasopharynx, the infratemporal fossa, the floor of the media fossa, or the parasellar region with little anterior progression. With bigger tumors, or when the tumor widely extends to the infratemporal fossa or the paranasal sinuses, we resort to a facial translocation approach by degloving. Sometimes, preauricular approaches can be combined with an endoscopic approach to remove the tumor after it has been detached at the top. As shown by our experience and by other authors, these procedures offer multiple operative corridors, good vascular control, and good chance to achieve radical resection. However, such procedures in advanced-stage disease (Andrews grade IV) add to the risk and morbidity. 6 After the initial surgery, the probability of recurrence seems to be related to the preoperative stage and, therefore, to the achievement of complete tumor resection. For early-stage disease (Andrews grade I III), recurrence rates range from 0% to 10%. 4,7 However, recurrence rates of advanced-stage lesions (Andrews grade IV) are higher and range from 5% to 40% even with aggressive approaches. 6,7 The radicality of surgery does not seem to avoid incomplete resection of some advanced JNAs, but potential development of complications increases significantly. We believe that in the case of tumors involving structures such as the optic chiasm, cavernous sinus, or orbit, the proper attitude should be to remove as much tumor as possible without causing morbidity. However, the remnant tumor can grow back and cause symptoms. In some published works, the treatment of residual tumor is debated because the behavior of such remnants is difficult to predict. Zhang et al 8 reported intracavernous residual tumors in 4 of 20 patients undergoing surgery and, after a prolonged follow-up period, showed a stable or decreasing mass in all of these patients. Other authors have also reported the same experience. 7 Nevertheless, this favorable behavior is not always observed and we consider that, in most cases, active treatment of the residual tumor is justified. We prefer additional surgery for extracavernous remnants but the treatment of those residual tumors close to the intracavernous internal carotid artery is controversial because they are usually poorly symptomatic and difficult to remove without morbidity. The removal of vital structures such as the cavernous sinus or internal carotid artery is not indicated. Onerci et al 9 suggest that a "wait and see'' approach may be preferable to craniofacial resection if there is residual intracranial tumor after surgery. However, his series was composed only of 4 patients with stage IIIa tumors and the intracranial penetration was limited. Therefore, long-term control of advanced-stage JNA with this strategy will require further prospective studies. We agree that, in case of patients with residual intracranial disease, a second surgery is considered the best option if the tumor can be reasonably extirpated. However, they should not be routinely operated on because complete removal of the tumor from the cavernous sinus would cause a significant morbidity that would hardly be justified during excision of a benign tumor. Because JNAs are tumors arising in the young population, tumor remnants might grow during the patient's lifetime and cause uncontrollable hemorrhage and neurological deficits. Therefore, we believe that the residual tumor should be treated and the radiosurgical procedure is a good option with acceptable morbidity. However, the roles of the "wait and see'' strategy and radiosurgery will require further prospective studies. Safer treatment options have been proposed for the treatment of intracavernous residual tumor. Radiation therapy has been used for patients who present recurrent disease, failure of complete tumor removal, or when the tumor involves vital structures such as the cavernous potion of the internal carotid artery or extensive intracranial invasion with high surgical morbidity. 10 In published works, the use of radiation therapy in JNAs in first intention obtains up to 85% long-term tumor control rate after 212 HEAD & NECK DOI /HED FEBRUARY 2013

5 ADVANCED-STAGE JUVENILE NASOPHARYNGEAL ANGIOFIBROMAS applying 30 to 35 Gy in advanced stages (Andrews grade IV) Cummings et al 11 reported 1 of the largest series of patients treated primarily with radiation therapy. The local control rate was 80%, with all recurrences being salvaged with surgery or additional irradiation, for an ultimate local control rate of 100%. Unfortunately, in the largest published series of patients with JNAs treated with radiation, it is not adjusted for stage and it is difficult to determine a treatment scheme according to tumor stage and compare the results with other studies. However, the main concerns regarding the use of radiation therapy for JNAs include toxicity to surrounding structures and the patients' young age at the time of therapy. Two of 55 patients reported by Cummings et al 11 developed malignancies and Reddy et al 14 reported 3 cases of cataracts and 1 case of carcinoma of the skin in a series of 15 patients. Because radiation may potentially cause longterm adverse effects, conventional radiotherapy should be avoided. Radiosurgery may offer therapeutic advantages over conventional radiotherapy for the treatment of residual tumor after surgery, considering the potential growing of these lesions and the difficulty to perform a safe resection. In stereotactic radiosurgery, a high-power radiation beam is projected onto the target with much greater accuracy minimizing the dose to surrounding normal critical structures such as the pituitary gland or optic nerves. Radiosurgery does not remove the tumor but destroys tumor cells or stops growth of active tissue. Usually, treatment is performed in a single-session and the safety of radiosurgery in the management of pediatric head and neck tumors has been confirmed. The management of JNAs with radiosurgery has recently been introduced by Dare et al 15 who reported 2 cases of successful gamma knife radiosurgery application in residual tumors after surgical resection. The median duration of follow-up was 36 months after treatment with radiosurgery. They did not report evidence of toxicity in either patient. However, the follow-up period was too short to detect secondary malignancies and late toxicity. Gamma knife radiosurgery should be administered as soon as the patient recovers from surgery. The time interval between surgery and gamma knife radiosurgery ranged from 2 to 7 months, as observed in previous studies. 15 In our population, we used gamma knife radiosurgery. The treatment was well-tolerated by all patients and, after mean follow-up of 15 years, secondary malignancies have not been detected. We did not detect remarkable late side effects, which confirm the safety of radiosurgery. The length of follow-up in our study was adequate to address toxicity after radiosurgery but the follow-up period was still too short to detect malignancies. However, the rate of the radiation-induced malignant changes is rarely described after radiosurgery and longterm follow-up is mandatory. Usually, JNAs recur within 6 to 36 months after primary therapy. During our 3-year minimum follow-up, we observed the absence of disease progression in all patients and, in 3 patients, there was a regression of the tumor, which confirms the effectiveness of our protocol. In conclusion, the satisfactory clinical results obtained from the present series support that an appropriate strategy in the management of advanced JNAs is surgical resection to shrink the tumor to a size suitable followed by the treatment with radiosurgery in locations in which surgery causes significant morbidity. We believe that this alternative is potentially safe and effective and should be taken into account. 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