Vascular tumors are a relatively rare entity in head and neck neoplasms. Angiofibromas account for most of these tumors. A summary of current staging systems is given. Management of angiofibroma is primarily endoscopic endonasal surgical resection, with preoperative embolization in most cases. The endonasal endoscopic transpterygoid approach is a useful technique in this scenario. The role of hormonal and targeted therapy is currently mainly adjuvant and requires further evaluation. A brief discussion of other vascular tumors is also provided.
34 Angiofibromas and Other Vascular Tumors of the Skull Base
Vascular tumors of the skull base, primarily angiofibromas, pose a significant surgical challenge because of their anatomical position, potential for expansion and bony destruction, and potential for significant perioperative bleeding. Methodical and systematic planning, exercising of sound surgical principles and technique, and provision of comprehensive perioperative care can help in surmounting these drawbacks. Angiofibroma is the most commonly encountered vascular tumor in this region. “Juvenile nasopharyngeal angiofibroma”1 should be considered a misnomer, as it neither exclusively occurs in the juvenile age group nor truly arises from the nasopharynx.
The gross tumor specimen appearance can range from small and smooth to large and multilobulated, with color anywhere from light tan to reddish/purple. Erosions and ulcerations can be commonly seen on the surface of this tumor, if large. Histologically, it consists of two components: fibrous stroma and vascular spaces. The fibrous stroma is composed of spindle-shaped cells in a dense collagen matrix. Within this dense matrix is a vast network of irregular vascular channels of variable size. These endothelial-lined spaces lack the surrounding smooth muscle that is normally seen in blood vessels, which is the likely cause for the significant hemorrhage that occurs following manipulation.
The most common presentation of a sinonasal angiofibroma includes painless nasal obstruction, recurrent unilateral epistaxis, and a sinonasal or nasopharyngeal mass. The epicenter of the tumor origin is the lateral basisphenoid, between the sphenoid sinus and pterygopalatine fossa, in the region of the sphenopalatine foramen.2 , 3 From its site of origin, it expands and erodes surrounding bone, taking the path of least resistance. It preferentially follows preformed pathways, medially to the nasal cavity, nasopharynx, and sphenoid sinus; laterally to the pterygopalatine fossa, gaining further access to the infratemporal fossa, as well as to the orbit via the inferior orbital fissure; anteromedially into the maxillary and ethmoid sinus; and posteriorly/superiorly along the foramina of the vidian canal and foramen rotundum toward middle cranial fossa. Direct extension intracranially is also possible, eroding through the cribriform plate, fovea ethmoidalis, and planum sphenoidale.4
Other vascular tumors of the head and neck region include hemangioma, tufted angioma, glomangiopericytoma, angiosarcoma, and vascular polyps. Hemangioma, which usually presents in the infantile period, primarily affects the upper airway (subglottis of larynx), sinonasal tract, and nasal dorsum and has not been reported to originate in the skull base region. Similarly, tufted angioma and acquired lobular capillary hemangioma (pyogenic granuloma) affect primarily the cutaneous regions and anterior nasal cavity and do not generally originate in the skull base. Later in this chapter, we describe glomangiopericytoma (a distinct form of hemangiopericytoma) and angiosarcoma, two entities that have a predilection for the skull base.
34.2 Incidence and Epidemiology
Angiofibroma is a rare tumor, accounting for less than 0.5% of all head and neck neoplasms. A national study from Denmark noted an incidence per year of 3.7 cases per million males aged 10 to 24 years between 1981 and 2003.5 It occurs mostly in adolescent males aged between 11 and young adulthood, although there have been reports of cases ranging from 6 years to 43 years, confirmed by histology.6 In a recent systematic review, the mean age of presentation was 17.2 years.7 There have been reports of this disease occurring in women, but these are rare instances and probably represent misreporting of other types of fibrovascular tumors rather than true angiofibromas. The data seem skewed toward larger case series from more populous countries, such as India and China, but the evidence does not suggest that angiofibroma exclusively involves any one ethnic group.8
The pathological classification and etiology of angiofibromas have historically been points of disagreement and confusion among researchers owing to their relative rarity and unique morphology, as well as uncertainty about their etiology. Histologically, they consist of abundant fibroblastic stroma within which are embedded vascular channels of various sizes, ranging from capillaries to sinuses.9 Clinically, angiofibromas exhibit locally aggressive characteristics. Angiofibroma has been variously described as hemangioma, vascular malformation,10 hyperplastic lesion in response to inflammatory or allergic stimulus, excessive growth of paraganglionic tissue,11 hamartoma,12 and even extracolonic manifestation of familial adenomatous polyposis.13 However, controversy remains over whether angiofibroma represents a hemangioma/vascular tumor or a vascular malformation.
As far back as 1982, Glowacki and Mulliken14 published a histology-based classification of vascular lesions, essentially dividing this vast group of conditions into two groups—hemangiomas or vascular malformations. The key differentiating factor was histological evidence of increased mitotic activity and endothelial proliferation resulting in hyperplasia in the former, but no such proliferative activity, with normal mitotic activity, in the latter. In the modern era of immunohistochemical techniques for differentiating cell lines, the ability to detect proliferative markers with the aid of monoclonal antibodies has helped clarify this matter.
In vascular lesions, such as angiofibroma, markers for angiogenic stimulation would be the best indicators of vascular proliferation. These include VEGF (vascular endothelial growth factor), VEGFR or Flt-1/Flk-1 (vascular endothelial growth factor receptor), and CD34 antigen, as well as other associated proliferative indicators, such as FGF (fibroblast growth factor) and PCNA (proliferating cell nuclear antigen).15 Multiple studies have confirmed that VEGF is the most prominent proangiogenic marker of this group.16 , 17
In 1994, Takahashi and colleagues found that FGF and VEGF protein levels were elevated in hemangiomas. By contrast, vascular malformations did not express bFGF and VEGF.18 In 2006, Saylam and colleagues analyzed the VEGF immunoreactivity of 27 angiofibroma samples and concluded that Juvenile nasopharyngeal angiofibroma (JNA) was a vascular and proliferative tumor.19 More recently, Zhang and colleagues20 identified immunoreactivity of CD34 in both JNA and OCH (orbital cavernous hemangioma, also a misnomer, as histologically it has been better characterized as a vascular malformation). However, the CD34 immunostaining was significantly higher in JNA than in OCH. Such findings support the view that JNA has a characteristic of vasoproliferative activity, more consistent with a vascular tumor than with vascular malformation.
Another area of dispute is whether the neoplastic component of the tumor arises from the vascular component or from the fibroblastic stroma. Proponents of the vascular component theory suggest that incomplete regression of the first branchial arch artery results in the persistence of a residual vascular network in the region of the sphenopalatine foramen, which under the influence of hormonal surges in the periadolescent period results in tumor growth.21 However, immunohistochemical studies have not consistently confirmed the relationship of positive hormone receptor status (e.g., androgen, estrogen, progesterone) within these tumors.19 , 22 , 23 Conversely, increasing evidence suggests that the fibroblastic stroma is instead the focus of the neoplastic transformation. This is suggested by the immunohistochemical localization of beta-catenin only to the nuclei of stromal cells rather than to endothelial cells.24
Of interest, angiofibromas have been reported to occur up to 25 times more frequently among patients who have familial adenomatous polyposis. This finding suggests that alterations of the adenomatous polyposis coli (APC)/beta-catenin pathway may be involved in the pathogenesis of angiofibroma.13 , 25
34.3.2 Other Vascular Tumors
Glomangiopericytoma (GPC), previously categorized as a sinonasal variant of hemangiopericytoma, is now considered a distinct tumor type under the 2005 World Health Organization classification of head and neck tumors.26 The unencapsulated tumor is present beneath an intact respiratory epithelium, unless it has eroded through. The characteristic appearance is that of a “patternless” diffuse architecture, which may efface or surround normal tissue. The pattern of arrangement of the cells includes short fascicles, reticular pattern, or short palisades of closely packed cells. These cells are separated by a rich vasculature ranging from capillaries to large patulous spaces, giving the characteristic “staghorn” or “antlerlike” configuration. Other features include low mitotic activity (< 3/hpf), with absent to mild nuclear pleomorphism, mast cells, eosinophils, and extravasated erythrocytes. Necrosis and atypical mitoses are typically absent.27
The immunohistochemistry profile of GPCs includes reactivity with smooth muscle actin (SMA), nuclear b-catenin, cyclin-D, vimentin, and factor XIIIA (strong and diffuse reaction for the first of these three). It lacks expression of CD34, CD31, FVIII-R Ag, CD117, STAT6, bcl-2, AE1/AE3, CK7, EMA, desmin, S100 protein, GFAP, CD68, CD99, and NSE.
GPCs are a rare entity, accounting for less than 0.5% of all tumors in the sinonasal and skull region.28 Several hundred cases have been reported in the literature, the majority of which have arisen within the nasal cavity and inferior/middle turbinates. The sinuses and skull base/intracranial extension have been involved less frequently. In an Armed Forces Institute of Pathology (AFIP) review of 104 GPC tumors, age at presentation was 5 to 86 years, with a mean of 62 years and approximate equal distribution of males/females.28 Presenting symptoms include nasal obstruction and epistaxis, as well as rhinorrhea, facial pain, and infraorbital region numbness. Gross tumor appearance is polypoid, nontranslucent, beefy red to grayish pink, soft, edematous, and fleshy to friable in texture.
Treatment of GPCs is primarily surgery, even in the case of recurrences. Large case series have alluded to excellent 5-year survival of 90%29 , 30 when complete surgical resection of the tumor has been achieved. Radiation treatment is generally reserved for unresectable disease.
Angiosarcoma is a rare, high-grade malignant vascular tumor that accounts for less than 0.1% of all sinonasal malignancies and for 2% of all sarcoma.31 In 10 cases of sinonasal tract angiosarcomas from AFIP, with age ranging from 13 to 81 years and almost equal male/female involvement, 8 arose from the nasal cavity and 2 from the maxillary sinus. The gross appearance of the tumor is vascular, generally purple to red, soft and friable, and it is often ulcerated with associated hemorrhage and necrosis. Microscopy reveals anastomosing vascular channels that appear tortuous and irregular, with small to large cavernous spaces. The endothelial cells are atypical, exhibiting pleomorphic nuclei with irregular nuclear contours and mitotic figures. Immunohistochemistry is characterized by immunoreactivity with Factor VIII-RA, CD34, CD31, and SMA but is nonreactive with keratin and S-100 protein. Ki67 is usually reactive (> 10%).32
Clinical presentation includes epistaxis, nasal obstruction, and nasal discharge. Treatment involves surgical resection, with possible adjuvant radiation and chemotherapy. Local recurrence following surgical resection occurs in more than 50% of cases and is the most common pattern of treatment failure. The majority of recurrences become apparent within 2 years of initial treatment. Regional metastases are less common, occurring in less than 20% of cases in most large series. Cervical lymph node metastases are more common in lesions arising from the scalp, and regional lymph node dissection is recommended in patients who have scalp lesions or palpable lymphadenopathy. Distant metastases occur in 30 to 50% of cases, with the lungs and liver most frequently involved. The overall 5-year survival for sinonasal angiosarcoma is generally poor, ranging from 12 to 33%.33
Traditional chemotherapy regimens have not been established but have included a combination of ifosfamide, paclitaxel, and doxorubicin for soft tissue sarcomas.34 Bevacizumab, a humanized monoclonal antibody against VEGF, has shown some promise in helping to control inoperable cases of angiosarcomas of the head and neck in a few case reports.
For angiofibroma, imaging studies play a determining role in its diagnosis and staging. The anatomical detail that can be obtained from modern imaging has obviated the need to biopsy these lesions, thereby avoiding serious or catastrophic bleeding in the office. Biopsies are usually sent from the operating room after embolization. A combination of CT (provides bony anatomical detail) with MRI (provides good soft tissue detail, differentiates tumor from secretions, and is particularly useful for suspected orbital or intracranial extension) ascertains the extent of tumor spread.
Historically, several staging systems have been described for angiofibromas. The Andrews35 and Radkowski36 systems (largely based on the Sessions37 system described 15 years earlier) have been the most widely used, as evidenced in a systematic review on this subject.7 Other systems have been described, including the Fisch,38 Chandler,39 and Onerci40 systems. Earlier systems did not consider the radiological features of modern imaging techniques and so have limited use. More recently, Snyderman and colleagues published the UPMC (University of Pittsburgh Medical Center) staging system.41 This system considers the presence or absence of residual vascularity after embolization, indicating the possible recruitment of vessels beyond the internal maxillary artery, including the internal carotid artery or bilateral blood supply. In general, we prefer the Andrews and UPMC systems to stage angiofibroma. A summary of these staging systems is offered in Table 34.1.
Staging for angiosarcoma does not follow the American Joint Committee on Cancer (AJCC) system, which is applied to other soft tissue sarcomas. At present, there is no accepted staging for sinonasal angiosarcoma, although lymph node and distant metastasis is not common at initial presentation. Similarly, although a grading system of grades I through III is used in soft tissue angiosarcoma, this system has not been applied to sinonasal angiosarcoma. Grading has not yet been proven to have a clinical prognostic significance in sinonasal tract angiosarcomas, although further evaluation with a larger number of cases has been suggested.42
The mainstay treatment of angiofibromas and most other vascular tumors is surgery, but age, symptoms, and expected prognosis also influence the decision, especially for benign tumors. Surgical approaches for angiofibroma resection can be broadly classified into external and endonasal endoscopic approaches. External approaches may follow an anterior route, via midfacial degloving/endonasal, transantral, Denker’s approach, or LeFort I or via Weber-Ferguson type incision, or a lateral route, via an infratemporal approach,43 with or without a craniotomy (for cases of significant intracranial invasion). Inferior transpalatal approaches have also been described but have mostly fallen into disuse. Small tumors may be exposed and removed by removing the ipsilateral hard palate after raising the mucoperiosteum in a U-shaped fashion; however, these tumors are amenable to an endoscopic resection, which is associated with fewer sequelae and complications. Removal via transpalatal approaches that divide the soft palate were abandoned due to poor visualization of the tumor, association with significant blood loss, and negative effect on speech quality secondary to soft palate fibrosis and scarring. To determine the best surgical approach, one must consider multiple factors related to tumor (stage), patient, and surgeon/institution.
The endonasal endoscopic approach has become the preferred option to resect these tumors today in view of the better visualization, lower morbidity, lack of external scars, and lower level of blood loss. Nonetheless, although many of these tumors can in principle be resected via an endonasal endoscopic approach, whether they can be in practice depends on the level of expertise and resources available at a given institution. Most authors agree that patients whose tumors correspond with up to Andrews stage IIIa are candidates for an endoscopic endonasal approach. However, endoscopic approaches have also been described for resecting stage IIIb tumors (intracranial, extradural extension).44 Table 34.2 summarizes the literature regarding endoscopic removal of angiofibromas over the past 15 years, analyzing the stage of tumor resected, rates of persistent/recurrent disease, and operative blood loss. Excluded from analysis were case series involving fewer than 10 patients, those in which tumor stage was not provided, and those involving inadequate or absent follow-up data.
The Endonasal Endoscopic Transpterygoid Approach
The endonasal endoscopic transpterygoid approach (EETA) is the initial surgical gateway that allows access to a variety of lateral and posterior surgical targets, including the infratemporal fossa (ITF), lateral nasopharynx (fossa of Rosenmuller), middle cranial fossa/Meckel’s cave, cavernous sinus, petrous internal carotid artery (ICA), and foramen lacerum. We define the transpterygoid approach as one that requires either partial or complete resection of the pterygoid plates process. Its technical nuances have been previously described.33 For a better understanding of its various modification and indications, the EETA (Fig. 34.1)45 has recently been classified into zones A–E, which match the extent of the transpterygoid dissection required by the surgical target (Table 34.3).46
The most pertinent EETA types to this discussion are type D (partial or complete removal of the pterygoid plates and dissection of the petrous ICA), which is used for lesions requiring access to the infratemporal fossa and control of the petrous ICA, and type E (involving the removal of Eustachian tube in addition to the dissection involved in type D), which is used when access to the lateral nasopharynx is required.
Tumors that extend beyond Andrews stage IIIa (generally considered advanced-stage) may require staging the tumor resection. This may involve partial resection followed by a completion endonasal surgery at a later time or combination of an endonasal endoscopic approach with an external approach.