Tumors of the Upper Respiratory Tract

Definition

These are benign neoplasms of surface epithelial derivation with varying growth patterns composed of multilayered epithelium with mucocytes and transmigrating inflammatory cells. Three morphologically distinct types, collectively referred to as sinonasal (schneiderian) papillomas, are identified and include exophytic (septal), inverted, and oncocytic (cylindrical or columnar cell) types ( Table 4A.1 ).

Clinical Features

Collectively, sinonasal papillomas represent fewer than 5% of all sinonasal tract tumors. The literature indicates that, among sinonasal-type papillomas, the septal papilloma is the most common type. However, practical experience indicates that the inverted type is the most common subtype seen. The oncocytic type is the least common. In general, the sinonasal-type papillomas occur over a wide age range but are rare in children. Inverted papillomas are most common in the fifth to eighth decades; cylindrical papillomas occur in a somewhat older age range (>50 years) and are uncommon in patients younger than the fourth decade of life; septal papillomas tend to occur in a younger age group. The septal papillomas almost invariably are limited to the nasal septum. Inverted papillomas occur along the lateral nasal wall (middle turbinate or ethmoid recesses) with secondary extension into the paranasal sinuses (maxillary and ethmoid, and less often sphenoid and frontal); less frequently, inverted papillomas may originate in a paranasal sinus. Oncocytic papillomas also are most often seen along the lateral nasal wall but may originate within a paranasal sinus (maxillary or ethmoid). The inverted and oncocytic subtypes rarely occur on the nasal septum. Typically, the sinonasal papillomas are unilateral; bilateral papillomas, in particular the inverted subtype, may occur with a reported incidence of up to 10%. In the presence of bilaterality, clinical evaluation to exclude the possibility of extension from unilateral disease (i.e., septal perforation) should be undertaken. Inverted papillomas may occur in a paranasal sinus without involvement of the nasal cavity.

Sinonasal papillomas have a tendency to spread along the mucosa into adjacent areas. Symptoms vary according to site of occurrence and include airway obstruction, epistaxis, an asymptomatic mass, and pain.

Etiology

Human papillomavirus types 6/11, less often 16/18, and rarely other HPV types (e.g., HPV-57) have been found in septal and inverted papillomas. A meta-analysis of inverted papillomas (760 cases) reported that 38.5% were HPV positive by either in situ hybridization or polymerase chain reaction. The use of p16 expression, an accepted surrogate biomarker for high-risk HPV infection in oropharyngeal carcinoma, is controversial in sinonasal papillomas, but generally it is not considered useful with no correlation between p16 staining and HPV. Whether a cause and effect exists between the presence of HPV and the development of sinonasal papillomas remains to be determined. Molecular biologic analysis of oncocytic papillomas to date has not identified the presence of HPV. No association is found with the development of additional papillomas elsewhere in the upper respiratory tract. Epstein-Barr virus has also been identified in inverted papillomas, possibly implicating EBV in the development of these tumors ; however, other studies failed to confirm the presence of EBV in tumor cells.

Treatment and Prognosis

The treatment for all sinonasal-type papillomas is complete surgical excision, including adjacent uninvolved mucosa. The latter is necessary as growth and extension along the mucosa result from the induction of squamous metaplasia in the adjacent sinonasal mucosa. This group of neoplasms will recur if incompletely resected; recurrence probably represents persistence of disease rather than multicentricity of the neoplasm. In general, prognosis is good after complete surgical excision; however, if left unchecked, these neoplasms have the capability of continued growth with extension along the mucosal surface with destruction of bone and invasion of vital structures.

Complications associated with sinonasal papillomas (inverted and oncocytic types) include recurrence and malignant transformation. The incidence of malignant transformation varies by subtype: Malignant transformation reported for the inverted subtype ranges from 2% to 27% ; for the oncocytic subtype the range is from 4% to 17% ; malignant transformation in septal papilloma rarely if ever occurs. Most malignancies occurring in association with schneiderian papillomas are squamous cell carcinomas (SCCs) (keratinizing and nonkeratinizing), varying in appearance from well to poorly differentiated. Less frequently, other carcinomas may occur, including verrucous carcinoma, mucoepidermoid carcinoma, small cell carcinoma, adenocarcinoma (nononcocytic, oncocytic), and sinonasal undifferentiated carcinoma. The carcinoma may occur synchronously or metachronously with the papilloma; metachronous carcinomas develop with a mean interval of 63 months (range 6 months to 13 years) from the onset of the papilloma to the development of the carcinoma. The carcinomatous foci may be limited or extensive. In one series, the development of metachronous carcinoma in sinonasal papillomas was always preceded by recurrence of the papilloma. There are no reliable histologic features that predict which papillomas are likely to become malignant. Papillomas with increased cellularity, pleomorphism, and increased mitotic activity do not necessarily become malignant. The presence of moderate to severe epithelial dysplasia is a potential indicator of malignant transformation. Similarly, surface keratinization and dyskeratosis have anecdotally been considered as possible predictors of malignant transformation. No correlation exists between the number of recurrences and the development of carcinoma.

Pathology

Sinonasal Papilloma, Septal Type

Macroscopic Appearance.

Septal papillomas are papillary, exophytic, verrucoid lesions with a pink to tan appearance and a firm to rubbery consistency. They are often attached to the mucosa by a narrow or broad-based stalk.

Microscopic Appearance.

Histologically papillary fronds are seen, being composed of a thick epithelium that is predominantly squamous (epidermoid) and, less frequently, respiratory type ( Fig. 4A.1 ). Surface keratinization is uncommon. Mucocytes (goblet cells) and intraepithelial mucous cysts are present. The stromal component is composed of delicate fibrovascular cores.

Sinonasal Papilloma, Inverted Type

Macrosocpic Appearance.

Inverted papillomas are large, bulky, translucent masses that are red to gray, varying from firm to friable in consistency.

Microscopic Appearance.

Histologically, these tumors have an endophytic or inverted growth pattern consisting of markedly thickened squamous epithelial proliferation growing downward into the underlying stroma ( Fig. 4A.2 ). The epithelium varies in cellularity and is composed of squamous, transitional, and columnar cells (all three may be present in a given lesion) with admixed mucocytes (goblet cells) and intraepithelial mucous cysts. A mixed chronic inflammatory cell infiltrate characteristically is seen within all layers of the surface epithelium. The cells are generally bland in appearance with uniform nuclei and no piling up. However, pleomorphism and cytologic atypia may be present. The epithelial component may demonstrate extensive clear cell features indicative of abundant glycogen content. Mitotic figures may be seen in the basal and parabasal layers, but atypical mitotic figures are not seen. Surface keratinization may be present. The stromal component varies from myxoid to fibrous with admixed chronic inflammatory cells and variable vascularity.

Sinonasal Papilloma, Oncocytic Type

Macroscopic Appearance.

Sinonasal papillomas, oncocytic type, are dark red to brown, papillary or polypoid lesions.

Microsocpic Appearance.

Histologically a multilayered epithelial proliferation is seen, composed of columnar cells with abundant eosinophilic and granular cytoplasm ( Fig. 4A.3 ). The nuclei vary from vesicular to hyperchromatic; nucleoli are usually indistinct. The outer surface of the epithelial proliferation may demonstrate cilia. Intraepithelial mucin cysts, often containing polymorphonuclear leukocytes, are seen; cysts are not identified in the submucosa. The stromal component varies from myxoid to fibrous with admixed chronic inflammatory cells and variable vascularity.

Differential Diagnosis

The differential diagnosis for septal papillomas includes verruca vulgaris and squamous papilloma. In contrast to all of the sinonasal-type papillomas, squamous papilloma of the nasal vestibule does not have mucocytes as part of the neoplastic proliferation. The differential diagnosis for inverted papillomas includes inflammatory sinonasal polyps, nonkeratinizing respiratory (transitional) carcinoma, and verrucous carcinoma. The differential diagnosis for oncocytic papilloma includes rhinosporidiosis and (low-grade) papillary adenocarcinoma. The differential diagnosis for exophytic (septal) papilloma is primarily with a cutaneous squamous lesion (e.g., papilloma, verruca) arising distal to the limen nasi from cutaneous mucosa.

Definition

These are benign exophytic, papillary, or verrucoid overgrowths of surface epithelium.

Clinical Features

Squamous papillomas represent the most common benign neoplasms of the upper aerodigestive tract mucosa and are commonly seen in the oral cavity and larynx. Less often, squamous papillomas occur in the pharynx and nasal vestibule. Squamous papillomas occur over a wide age range but most commonly in adults; there is no gender predilection.

Treatment and Prognosis

Recurrences occur infrequently and relate to inadequate excision. Malignant transformation does not occur.

Pathology

Definition

This is a benign salivary gland tumor comprised of epithelial and myoepithelial cells, and a variable amount of chondromyxoid stroma.

Clinical Features

Pleomorphic adenomas tend to originate along the nasal septum (bony or cartilaginous component) more than any other site. Although these tumors may arise from within the paranasal sinus, more often paranasal sinus involvement occurs as a result of extension from an intranasal lesion.

Treatment and Prognosis

Surgery is usually curative with local recurrence being seen in fewer than 10% of patients. Rarely, malignant transformation may occur (i.e., carcinoma ex pleomorphic adenoma), characterized by overtly malignant cytomorphology and/or infiltrative growth. The latter may include neurotropism or osseous invasion.

Pathology

Microscopic Appearance.

As is true of all upper aerodigestive tract minor salivary gland tumors (benign or malignant), the pleomorphic adenomas are unencapsulated. However, in contrast to malignant minor salivary gland tumors, these tumors are relatively circumscribed without invasive growth; involvement of surface epithelium does not constitute invasion. Histologically, these tumors are identical to those of major salivary glands (see Chapter 7 ), including an admixture of ductular or tubular structures, spindle-shaped myoepithelial cells, and a chondromyxoid stroma. A tendency exists for pleomorphic adenomas of the nasal cavity to be cellular, with a predominant myoepithelial component, usually in the form of plasmacytoid (hyaline cell) rather than spindle-shaped myoepithelial cells ( Fig. 4A.4 ).

Differential Diagnosis

The diagnosis of PA is usually straightforward. However, in limited tissue sampling with tissue fragmentation that often occurs in initial biopsies of such lesions, differentiation from other salivary gland tumors, including malignant ones, may be problematic especially in cellular PAs. In the absence of features allowing for a definitive diagnosis, a diagnosis of “minor salivary gland neoplasm, not further specified” would be advised with a recommendation for complete resection to include tumor-free margins. A definitive diagnosis should be achievable with the availability of the entire tumor for histologic review.

Given the presence of ductular or tubular structures and chondromyxoid stroma, these tumors would not be considered as myoepitheliomas. Myoepitheliomas represent a monomorphic adenoma showing only a single cell type, the myoepithelial cell. Typically, myoepitheliomas are of the spindle cell type and, rarely, the tumor cells are of the plasmacytoid type. Myoepithelial differentiation can be shown by immunoreactivity for cytokeratin, S100 protein, and smooth muscle actin, as well as more specific markers of myoepithelial differentiation, including p63 and calponin (see Fig. 4A.4 ).

Salivary gland anlage tumor (SGAT), also known as congenital pleomorphic adenoma, is an uncommon benign tumor with mixed epithelial and mesenchymal elements recapitulating in early stages in the embryology of salivary glands between 4 and 8 weeks of gestation and felt to be a hamartomatous lesion. SGATs are most common to males, usually present in the immediate neonatal period or in early infancy (by age 6 weeks) and are often located at or near midline in the nasopharynx. Histologically SGATs are comprised of multiple submucosal solid nodules separated by less cellular stroma and a network of delicate linear and branching small ductlike or glandular structures and nests of solid or cystic squamous epithelium set in a variably fibromyxoid stroma ( Fig. 4A.5 ). The epithelial components are reactive for cytokeratins (pancytokeratins, CK7) and p63 with EMA restricted to tubular structures. The mesenchymal components are reactive for vimentin, cytokeratins (AE1/AE3, CAM 5.2, CK7, OSCAR), p63, and muscle-specific actin but negative for S100 protein and GFAP. Consistent diffuse and widespread reactivity for salivary gland amylase is present. The proliferation rate (by Ki67 staining) may be as low as 1% or as high as 20% to 30%. Simple excision (polypectomy) is considered curative.

Definition

This is a benign tumor of pituitary cells arising in upper aerodigestive tract mucosal sites from remnants of Rathke pouch with no continuity/connection with the sella turcica. Pituitary neoplasms originating from the sella turcica may occasionally extend into the sinonasal tract or nasopharynx and appear to present as a primary neoplasm of those regions. Radiographic analysis will identify the lesion as originating from the sella turcica.

Clinical Features

EPAs occur in adults with no sex predilection and present with airway obstruction, chronic sinusitis, visual field defects, cerebrospinal fluid leakage, and endocrine manifestations (e.g., Cushing syndrome, hirsutism). The most common ectopic sites of occurrence are the sphenoid sinus followed by the nasopharynx. Other less common sites include the nasal cavity and ethmoid sinus; rarely EPAs that involve the clivus may clinically suggest a diagnosis of chordoma.

Treatment and Prognosis

Complete removal is curative without recurrent or progressive tumor, and with resolution of any endocrinopathy. Rarely, malignant transformation of ectopic pituitary adenoma may occur.

Pathology

Microscopic Appearance.

Histologically a submucosal epithelioid neoplastic proliferation is seen with solid, organoid, and trabecular growth patterns ( Fig. 4A.6 ). The epithelioid cells have round nuclei with a dispersed chromatin pattern and granular eosinophilic cytoplasm. Pleomorphism, necrosis, or mitotic activity is not seen. No evidence is seen of glandular or squamous differentiation.

Differential Diagnosis ( Table 4A.2 )

EPAs may be mistaken for olfactory neuroblastoma (ONB), especially ONBs that express cytokeratin. ONBs arise predominantly in the superior aspect of the nasal cavity and rarely originate from the sphenoid sinus, the most common location for EPA. Cytokeratin expression when present in ONBs tends to be limited (i.e., extent and/or intensity); the presence of diffuse and strong cytokeratin staining is unusual in ONB and should prompt consideration for a possible diagnosis of EPA. Carcinoid tumor (well-differentiated neuroendocrine carcinoma) may be confused with EPA but carcinoid tumors of the sinonasal tract are so uncommon as to be considered virtually nonexistent.

Paragangliomas (discussed next) rarely if ever occur in the sinonasal tract. In contrast to EPAs, the chief cells in paraganglioma are typically negative for pituitary hormone markers and cytokeratin, although rare cases of paraganglioma have been reported to be cytokeratin positive. Further, characteristic S100-protein staining is seen along the periphery of the neoplastic lobules in a sustentacular cell pattern of staining, a feature not seen in EPAs.

Definition

This is a benign neuroendocrine tumor arising from the neural crest–derived paraganglia of the autonomic nervous sytem.

Extraadrenal paragangliomas are identified throughout the body and classified according to the anatomic site of occurrence. Paragangliomas in the head and neck region include those of carotid body, jugulotympanic, and vagal origin (see Chapter 28 ).

Clinical Features

Paragangliomas may rarely occur in other mucosal sites of the upper aerodigestive tract, including the nasal cavity, where they produce nasal obstruction and/or epistaxis. Approximately 25% of parapharyngeal space tumors are paragangliomas. Parasympathetic paraganglia are found throughout the body and give rise to almost all of the paragangliomas of the upper aerodigestive tract. Most paragangliomas in this location are nonfunctional, although rare cases exist of adrenocorticotropic hormone–producing nasal paraganglioma associated with Cushing syndrome.

Treatment and Prognosis

The prognosis is excellent after complete resection. Although the majority of these tumors are benign and behave in an indolent manner, they may recur locally and be invasive. Rarely, these tumors are malignant. The histology is not predictive of malignant behavior, and malignancy in paraganglioma is determined most reliably by the presence of metastatic disease.

Pathology

Definition

This benign neoplasm of meningothelial cells most often occurs intracranially where it represents from 13% to 18% of all intracranial tumors.

Clinical Features

Meningioma occurring outside the central nervous system is considered ectopic; these meningiomas are divided into those with no identifiable central nervous system connection (primary) and those with central nervous system connection (secondary). The most common sites of occurrence of the ectopic meningiomas of the head and neck region include the middle ear and temporal bone, sinonasal cavity, orbit, oral cavity, and parotid gland. Sinonasal tract meningiomas most often involve the nasal cavity, or a combination of nasal cavity and paranasal sinuses ; less frequently, involvement may be isolated to the nasopharynx, frontal sinus, or sphenoid sinus. In the sinonasal cavity, symptoms include nasal obstruction, epistaxis, headache, pain, visual disturbances, and facial deformity. The tumors may erode the bones of the sinuses with involvement of surrounding soft tissues, the orbit, and occasionally the base of the skull.

Treatment and Prognosis

Complete surgical excision may be difficult to achieve, resulting in recurrence; recurrence rates range up to 30%. After the histologic diagnosis, it is essential to exclude spread from a primary intracranial neoplasm.

Pathology

Microscopic Appearance.

The histology is similar to that of its intracranial counterparts (see Chapter 26 ). Among the histologic subtypes of meningioma, the meningotheliomatous type is the most common in the sinonasal cavity ( Fig. 4A.7 ). Psammoma bodies, typical and numerous in intracranial meningothelial meningiomas, may be seen but are not as common in the ectopically located meningiomas.

Immunohistochemical Staining

The immunohistochemical profile of meningiomas includes reactivity with epithelial membrane antigen (EMA) and somatostatin receptor 2 (SSTR2A), with absence of cytokeratin or neuroendocrine markers (chromogranin and synaptophysin). Meningiomas may be reactive for p63. Initally, Rushing et al. reported that p63 expression correlated to tumor grade with lower grade meninigomas (World Health Organization [WHO] grade I) lacking expression while higher grade tumors (WHO grades II and III) showed increased expression. These authors posited that p63 expression might correlate to clinical outcome. Subsequently, Mittal et al. reported that a considerable number of WHO grade I meningiomas expressed p63 and that, while p63 expression was significantly associated with higher histologic grade, it was not considered as a sole biomarker to assess aggressive behavior in meningiomas.

Lobular Capillary Hemangioma (LCH)

Pathology

Macroscopic Appearance.

The gross appearance of LCH is a smooth, lobulated, polypoid red mass measuring up to 1.5 cm in diameter.

Microscopic Appearance.

Histologically LCH is characterized by a submucosal vascular proliferation arranged in lobules or clusters composed of central capillaries and smaller ramifying tributaries ( Fig. 4A.8 ). The central capillaries vary in caliber and shape, and in more mature lesions may show a staghorn appearance. The endothelial cell lining may be prominent and may display both endothelial tufting and mitoses. Surrounding and intimately associated with the vascular component are granulation tissue and a mixed chronic inflammatory cell infiltrate. The surface epithelium is often ulcerated with associated necrosis. In longstanding lesions, the lobular pattern is often lost. Increased mitotic activity may be present, but such a finding is not diagnostic for malignancy.

Immunohistochemical Staining.

Diagnosis of LCH and its differentiation from other lesions are usually accomplished by light microscopic evaluation, and immunohistochemical staining is generally not required. However, at times, immunohistochemical staining may be needed in the diagnosis and differential diagnosis of LCH. The neoplastic cells are reactive for CD31, CD34, factor VIII–related antigen, ERG, and FLI1. No staining is present for glucose transporter 1 (GLUT-1). In contrast to Kaposi sarcoma, staining for human herpesvirus 8 (HHV-8) is negative.

Other Hemangiomas

Cavernous hemangiomas occur less frequently in the upper respiratory tract when compared to capillary hemangioma. In general, cavernous hemangiomas have a similar clinical presentation to capillary hemangiomas but are more often identified in the turbinates, in the lateral nasal wall, or within bone (intraosseous) than in the nasal septum. Similar to cavernous hemangiomas at other sites, those of the sinonasal tract are composed of multiple, variably sized, dilated and thin-walled, endothelial cell–lined vascular spaces. Surgical resection is curative.

Definition

This is a benign neoplasm composed of an admixture of mature vascular and fibrous tissue with locally destructive properties. It is also referred to as juvenile angiofibroma.

Evidence suggests that this tumor does not originate from the nasopharynx, but from a fibrovascular nidus in the posterolateral wall of the nasal cavity and pterygopalatine fossa near the sphenopalatine foramen secondarily extending into the nasopharynx and other adjacent/contiguous anatomic sites. Given the presumed origin in the posterior nasal cavity, use of the designation “nasopharyngeal” is questioned.

Clinical Features

Angiofibroma is a relatively rare neoplasm, accounting for fewer than 1% of all head and neck tumors. This tumor occurs almost exclusively in men, and some believe it is a tumor limited to the male population. Angiofibromas occur over a wide age range but are most common in the second decade. They are uncommon over the age of 25 years. However, these tumors may rarely occur in older ages, thereby negating the use of the designation “juvenile” angiofibroma. The most common clinical complaints are persistent nasal obstruction and epistaxis. Late signs and symptoms include facial swelling or deformity (swelling of the cheek), nasal discharge, proptosis, diplopia, headache, sinusitis, cranial nerve palsies, anosmia, and hearing deficits. Pain is considered an unusual finding. Typically, symptoms have been present for more than 1 year before diagnosis. The site of occurrence is usually the posterolateral portion of the roof of the nasal cavity in the area of the sphenopalatine foramen. Large tumors may extend anteriorly into the nasal cavity, causing nasal obstruction and simulating a primary intranasal or paranasal sinus tumor. Extension posteriorly may fill the nasopharynx and extend into the oropharynx, causing displacement of the soft palate. Extension can occur through the sphenopalatine foramen with involvement of the pterygomaxillary fossa and infratemporal fossa, resulting in facial deformities. Extension into the middle cranial fossa can occur if the tumor involves and destroys the pterygoid process.

Pathogenesis

As a result of the overwhelming occurrence in men, this tumor is thought to be hormonally driven, being dependent on testosterone and inhibited with estrogen. Androgen receptors have been found in these tumors but not estrogen receptors. A familial predisposition for nasopharyngeal angiofibromas has been suggested in patients with familial adenomatous polyposis (FAP). Patients with FAP have nasopharyngeal angiofibroma 25 times more frequently than an age-matched population. Activating β-catenin mutation without APC gene mutation has been reported in sporadic nasopharyngeal angiofibroma. Zhang and colleagues found that expression of β-catenin, c-kit (CD117), and neural growth factor (NGF) was higher and more frequent in stromal cells of nasopharyngeal angiofibromas than those of nasal polyps. In a limited number of patients, consumptive coagulopathy has been found as a complication of nasopharyngeal angiofibromas suggesting that preoperative coagulation studies may be useful in ensuring perioperative hemostasis.

Imaging Findings

Routine radiographs show characteristic bowing of the posterior wall of the maxillary antrum, as well as distortion and posterior displacement of the pterygoid plates (Holman-Miller sign). Arteriographic findings are usually diagnostic and include a tumor with marked vascular hypertrophy and increased number of arteries without beading, dilatation, segmental narrowing, or aneurysmal dilatation. Radiographic staging of nasopharyngeal angiofibromas based on extent of disease has been proposed ( Tables 4A.3 and 4A.4 ).

Treatment and Prognosis

In uncomplicated cases (with tumor limited to the nasopharynx), surgical excision via a transverse palatal approach is the treatment of choice. Vascular embolization usually precedes surgical intervention to control bleeding. Recurrence rates vary from 6% to as high as 24%. High recurrence rates and early recurrence may occur in nasopharyngeal angiofibromas involving the skull base. Recurrences are more common in cases with intracranial extension. Tumor recurrence in cases without intracranial extension usually occurs within 2 years of treatment. In general, the prognosis is excellent after surgical removal; mortality rates range from 3% to 9%. Rarely, spontaneous regression may occur. Malignant (sarcomatous) transformation is a rare event and has been linked to treatment with radiotherapy (postirradiation sarcoma).

Pathology

Microscopic Appearance.

Histologically, angiofibromas are unencapsulated and are characterized by a fibrocollagenous stromal proliferation with an admixture of variably sized vascular spaces ( Fig. 4A.9 ). The vascular component is made up of thin-walled, small to large vessels varying in appearance from stellate or staghorn to barely conspicuous due to marked compression by stromal fibrous tissue. The endothelial cells form a single layer and are flat or plump in appearance. The vessel walls lack elastic fibers and are distinctive in having a smooth muscle layer which may be incomplete or discontinuous and which shows marked variation in thickness. Central areas of the tumor may be relatively hypovascular. The stroma is composed of fibrous tissue with fine or coarse collagen fibers. The stromal cells are spindle shaped and stellate with plump nuclei, and tend to radiate around vessels. Nuclear pleomorphism and multinucleate giant cells may be seen. Mitotic figures are rare. The stroma may be focally myxoid. Mast cells are common; however, other inflammatory cells are absent except near areas of surface ulceration. Tumors of longer duration tend to be more fibrous and less vascular.

Differential Diagnosis

The differential diagnosis includes sinonasal inflammatory polyps, lobular capillary hemangioma, benign peripheral nerve sheath tumor, solitary fibrous tumor, and extraabdominal (aggressive) fibromatosis. The previous detailed histologic findings, including characteristic vascularity, and immunophenotype should allow for the diagnosis of angiofibroma, differentiating it from these other lesions/tumors.

Definition

Solitary fibrous tumor (SFT) is a distinctive and ubiquitous fibroblastic type mesenchymal neoplasm with a hemangiopericytoma (HPC)–like vascular pattern that typically is serosal based or a soft tissue proliferation, but that may occur in extrapleural sites, including the upper aerodigestive tract. SFTs include those tumors formerly classified as hemangiopericytoma ; however, sinonasal-type HPC shares more features similar to glomangiopericytoma than to soft tissue HPC and is addressed separately later in this chapter.

Clinical Features

SFTs of the head and neck are rare tumors, most often involving the nasal cavity and paranasal sinuses. Patients with tumors in these sites present with nasal obstruction. Usually the symptoms have been present for an extended time (≥1 year).

Treatment and Prognosis

Complete surgical resection is curative. Recurrence is primarily due to incomplete resection. SFT of the nasopharynx may be more difficult to excise completely. Despite incomplete resection, these tumors are not generally associated with adverse biologic behavior at this anatomic location.

Pathology

Microscopic Appearance.

Histologically (see Chapter 24 ) they are unencapsulated and composed of a variably cellular proliferation of bland spindle-shaped cells lacking any pattern of growth and associated with ropey, keloidal collagen bundles and associated, often branching, thin-walled vascular spaces ( Fig. 4A.10 ).

Differential Diagnosis

The differential diagnosis primarily includes sinonasal HPC (see later discussion). Other tumors that need to be differentiated from SFT include smooth muscle tumors, nerve sheath tumors, and fibrohistiocytic tumors.

Definition

Schwannomas are benign (usually encapsulated) nerve sheath tumors composed of differentiated neoplastic Schwann cells and characterized by a cellular component (Antoni A) and a loose myxoid component (Antoni B) and presence of diffuse S100-protein immunoreactivity. Other terms for this neoplasm include neurilemoma, neurinoma, and conventional schwannoma .

Neurofibromas are well-demarcated but unencapsulated intraneural or diffusely infiltrative extraneural tumors consisting of an admixture of Schwann cells, perineurial cells, and fibroblasts.

Clinical Features

Benign peripheral nerve sheath tumors of the head and neck are common, perhaps accounting for as many as 45% of all cases. However, benign peripheral nerve sheath tumors of the sinonasal tract and nasopharynx are uncommon, accounting for fewer than 4%. In this location schwannomas are substantially more common than neurofibromas. Adults are most commonly affected, with no sex predilection. Patients present with symptoms related to nasal obstruction and epistaxis. Nasopharyngeal involvement may result in unilateral serous otitis media. In two of the cases reported by Hasegawa and colleagues, visual disturbances were present because of intracranial extension of the tumor. These tumors may cause pressure erosion of bone. No association with neurofibromatosis is seen.

Treatment and Prognosis

Surgical resection is the treatment of choice and is typically curative.

Pathology

Microscopic Appearance.

Unlike their soft tissue counterparts, benign schwannomas of the upper aerodigestive tract are unencapsulated ( Fig. 4A.11 ). Aside from this finding, the histologic features are similar to those described for benign peripheral nerve sheath tumors at other sites (see Chapter 27 ).

Neurofibromas are submucosal, circumscribed tumors composed of spindle-shaped cells with wavy or buckled, hyperchromatic nuclei and indistinct cytoplasm. An associated collagenized and/or myxoid stromal component is present.

Leiomyoma

Rhabdomyoma

Sinonasal Myxoma and Fibromyxoma

Pathology

Macroscopic Appearance.

Grossly, these are delineated but unencapsulated multinodular, gelatinous-appearing lesions.

Microscopic Appearance.

Histologically, these tumors show a scant, loosely cellular proliferation consisting of spindle-shaped or stellate-appearing cells embedded in an abundant mucinous stroma ( Fig. 4A.12 ). The nuclei are small and hyperchromatic. Cellular pleomorphism, mitotic figures, and necrosis are absent. The amount of collagenous fibrillary material varies between cases and, depending on the extent, the tumor may be called a fibromyxoma ( Fig. 4A.13 ). The periphery of the tumor appears circumscribed, but local infiltration with replacement of bone can be seen. Vessels are generally sparse.

Immunohistochemical Staining.

The neoplastic cells are vimentin positive but are negative for S100 protein, desmin, myogenin (myf4), MUC4, β-catenin, CD34, STAT6, and MDM2.

Definition

Osteomas are benign bone-forming tumors that are almost exclusively identified in the craniofacial skeleton.

Clinical Features

Sinonasal osteomas may be found throughout the sinonasal tract but most commonly involve the frontal and ethmoid sinuses. These tumors are usually asymptomatic and are found only by radiographic studies. Symptoms associated with paranasal sinus osteomas include headaches, facial swelling or deformity, and ocular disturbances. Sinonasal osteomas are more common in men and occur over a wide age range but are most often encountered in the second to fourth decades of life. Sinonasal osteomas usually occur as a single lesion but may be associated with Gardner syndrome, an inherited autosomal dominant trait characterized by intestinal (colorectal) polyposis, soft tissue lesions (fibromatosis, cutaneous epidermoid cysts, lipomas, leiomyomas), and multiple craniofacial osteomas. The radiographic appearance is that of a sharply delineated radiopaque lesion confined to bone or protruding into a sinus.

Treatment and Prognosis

Unless symptomatic, osteomas require no treatment. Complete surgical excision is curative.

Microscopic Appearance

Histologically, osteomas are well circumscribed and composed of dense, mature, predominantly lamellar bone sometimes rimmed by osteoblasts. Interosseous spaces may be composed of fibrous, fibrovascular, or fatty tissue, and hematopoietic elements may be present.

Ossifying Fibroma (OF)

Pathology

Macroscopic Appearance.

Ossifying fibromas appear as tan or gray to white, gritty, and firm, varying in size from 0.5 to 10 cm.

Microscopic Appearance.

Histologically ossifying fibro­mas are composed of randomly distributed mature (lamellar) bone spicules rimmed by osteoblasts admixed with a fibrous stroma ( Fig. 4A.14 ). Although the osseous component is generally described as mature, the central portions may be woven bone with lamellar bone at the periphery. Complete bone maturation is seldom seen. The fibrous stroma may be densely cellular; mitotic figures are rare to absent. Secondary changes, including hemorrhage, inflammation, and giant cells, may be seen.

Psammomatoid (Active) Ossifying Fibroma (POF)

Pathology

Microscopic Appearance.

The histology is that of a benign fibroosseous proliferation composed of bony spicules and spherules admixed with a fibrous stroma. The most distinctive component is the presence of mineralized or calcified psammomatoid bodies or ossicles ( Fig. 4A.15 ). These ossicles vary from a few in number to a dense population of innumerable spherical bodies. The ossicles are demarcated with a central blue to black appearance surrounded by a pink-appearing rim and with concentric laminations. The ossicles vary from small with a round to oval shape to being larger and irregularly shaped and are present within either the bony trabeculae or the adjacent cellular stroma. Osteoclasts are present within the ossicles, and osteoblasts can be seen along their peripheral aspects. The bony trabeculae vary in appearance and include odd shapes with a curvilinear pattern. The trabeculae are composed of lamellar bone with associated osteoclasts and osteoblastic rimming. Transition zones between the spherical ossicles and bony trabeculae can be seen. The nonosseous component includes a cellular stroma with a fascicular to storiform growth composed of round to polyhedral to spindle-shaped cells with prominent basophilic nuclei and inapparent cytoplasmic borders. Mitotic figures can be seen, but mitotic activity is not prominent. Giant cells can be seen among the psammomatoid ossicles or scattered throughout the nonosseous stromal component. Osteoid formation may be present focally.

Fibrous Dysplasia (FD)

Pathology

Microscopic Appearance.

Histologically the fibrous component is nondescript and of variable cellularity. The osseous component includes irregularly shaped trabeculae of osteoid and immature (woven) bone arising within the fibrous stroma—being poorly oriented with misshapen bony trabeculae, increased cellularity, and irregular margins—and forms odd geometric patterns, including C- or S-shaped configurations (so-called Chinese characters) ( Fig. 4A.16 ). The trabeculae typically lack osteoblastic rimming. Multinucleate giant cells, macrophages, increased vascularity, and calcification may be seen.

Cytogenetics and Molecular Genetics.

Guanine nucleotide-binding protein/α-subunit (GNAS) mutations are identified in fibrous dysplasia but are absent in ossifying fibromas, cementoossifying fibromas, cementoossifying dysplasias, and odontogenic myxomas.

Definition

A chondroma is a benign neoplasm of cartilage.

Clinical Features

Chondromas of the sinonasal tract and nasopharynx are rare. The most frequent sites of occurrence include the nasal septum and the nasopharynx. Sinus opacification or a circumscribed radiolucent lesion can be seen by radiographic studies.

Treatment and Prognosis

Surgical excision is curative; recurrences are uncommon.

Pathology

Ameloblastoma

Primary Sinonasal Ameloblastoma.

Sinonasal tract involvement is uncommon and usually occurs by secondary extension from the maxilla. However, true primary sinonasal ameloblastomas without connection to gnathic sites uncommonly occur. Schafer and colleagues reported a series of 24 primary sinonasal ameloblastomas. In their series a decidedly male preponderance of 3.8 : 1 was seen, with a mean age at presentation of 59.7 years (approximately 15–25 years later than in patients with ameloblastoma occurring within the jaws). The patients usually presented with a mass lesion and nasal obstruction. Sites of involvement included the nasal cavity only, the paranasal sinuses only, or both the nasal cavity and the paranasal sinuses.

In contrast to the characteristic multilocular and radiolucent presentation of ameloblastomas within the jaws, sinonasal ameloblastomas are described radiographically as solid masses or opacifications. Bone destruction, erosion, and remodeling (remnant of bony shell delimiting the lesion as it grew) may be present.

Treatment and Prognosis.

Surgical excision is the treatment of choice in all cases, but the type and extent of surgery vary. Schafer and colleagues reported a 22% recurrence rate. Recurrence of the tumor was generally within 1 to 2 years of the initial procedure, but in one of their patients the recurrence was 13 years after initial surgery. Overall treatment success correlated most positively with complete surgical eradication when performed in conjunction with thoroughly detailed radiographic imaging. No tumor deaths, metastases, or malignant transformation has been reported.

Pathology

Microscopic Appearance.

Histologically sinonasal ame­loblastomas are similar in appearance to their gnathic counterparts (see Chapter 6 ). The plexiform pattern, composed of a network of long anastomosing cords of odontogenic epithelium, represents the predominant histologic pattern ( Fig. 4A.17 ). The stellate reticulum-like component associated with other patterns of ameloblastoma is often less conspicuous in the plexiform histologic type. The acanthomatous pattern, characterized by squamous metaplasia and keratin formation in the central portions of the epithelial islands, can also be seen but is usually limited.

Other histologic types include follicular (solid and cystic), basaloid, and granular cell, the latter characterized by cells with brightly eosinophilic granular cytoplasm. These histologic subtypes can be found independently or within the same tumor. The ameloblastomatous proliferation can be seen arising in direct continuity with the intact sinonasal surface mucosal epithelium. The latter finding in conjunction with the absence of continuity with gnathic sites supports the histogenesis of these sinonasal tumors from totipotential cells of the sinonasal mucosal epithelium.

Differential Diagnosis.

Given their unusual localization to the sinonasal tract, the diagnosis of sinonasal ameloblastoma may be overlooked and may be confused with a variety of basaloid neoplasms, including sinonasal nonkeratinizing carcinoma, basaloid squamous cell carcinoma, salivary gland adenoid cystic carcinoma, HPV-related multiphenotypic sinonasal carcinoma, and craniopharyngioma. Attention to the characteristic central stellate reticulum and peripheral columnar-appearing cells with associated reverse polarity should be diagnostic.

Craniopharyngioma

Benign Teratoma

Definition

This sinonasal tumor shows perivascular myoid differentiation typically with an indolent biologic behavior. Also referred to as sinonasal-type hemangiopericytoma, hemangiopericytoma-like sinonasal tumor, and sinonasal glomus tumor.

The classification of this sinonasal tumor has evolved and continues to evolve from its designation for the last several decades as sinonasal hemangiopericytoma-like tumor reflecting the uncertainty of its relationship to soft tissue hemangiopericytoma to the more current suggested designation of sinonasal glomangiopericytoma reflecting a perivascular myoid differentiation. The current classification of soft tissue hemangiopericytoma incorporates it within the spectrum solitary fibrous tumor based on the presence of NAB2-STAT6 gene fusion and STAT6 immunoreactivity. Studies to date have shown that sinonasal glomangiopericytoma/hemangiopericytoma are negative for NAB2-STAT6 gene fusion and/or STAT6 immunoreactivity precluding classification within the spectrum of SFT and soft tissue hemangiopericytoma. Genetic abnormalities seen in association with glomus tumor include miR143-NOTCH fusions and GLI1 . Based on the genetic studies in the literature, including the absence of NAB2-STAT6 and the presence of miR143-NOTCH fusions, it would appear that the sinonasal glomangiopericytoma does not merit classification within the spectrum of SFT/soft tissue hemangiopericytoma but does merit the designation sinonasal glomangiopericytoma as used in the current WHO classification of head and neck tumors. Furthermore, these tumors are known to harbor CTNNB-1 (beta-catenin) gene mutations.

Clinical Features

Sinonasal glomangiopericytoma (SG) accounts for less than 0.5% of all sinonasal tract tumors. There is no sex predilection; it occurs over a wide age range but is most commonly seen in the sixth to seventh decades of life. SG typically presents as a unilateral nasal mass with obstruction and epistaxis. Extension into adjacent paranasal sinuses may occur, but isolated involvement of a paranasal sinus is uncommon. The radiologic appearance of sinonasal-type HPC is usually opacification of the involved sinus. Bone erosion due to pressure may be seen. Arteriographic findings reveal a richly vascular neoplasm. No known etiologic factors exist.

Treatment and Prognosis

Surgery is the treatment of choice. SGs are considered radioresistant neoplasms. SGs are indolent-behaving tumors with overall 5-year survival rates of greater than 90%. Local recurrence may occur in as many as 40% of cases and is likely due to inadequate surgical excision. Eichorn et al. and El-Naggar et al. report that recurrence of SG can be anticipated over extended follow-up periods (one to two decades). Aggressively behaving SGs are uncommon and include tumors that are locally destructive or are metastatic. Findings potentially linked to aggressive behavior include large tumor size (>5 cm), marked nuclear pleomorphism, increased mitotic activity (>4 mitoses per 10 hpf), necrosis, invasive growth (e.g., bone), and a proliferation index of greater than 10%, but some of these lesions may have been SFTs. Metastatic tumor occurs to regional lymph nodes and lung and is usually preceded by recurrent tumor, but predicting the biologic behavior is difficult (see Chapter 3 ).

Pathology

Microscopic Appearance.

Histologically SG is a submucosal, circumscribed but unencapsulated cellular tumor. In contrast to LCH, SG has a diffuse growth pattern and is composed of a single cell type distributed around endothelial-lined vascular spaces ( Fig. 4A.18 ). The tumor cells are usually arrayed in short fascicles and less often may show storiform, whorled, or even palisaded growth patterns. The tumor cells are usually uniform with round to oval nuclei, vesicular to hyperchromatic-appearing chromatin, and indistinct eosinophilic cytoplasm; occasionally, spindle-shaped cells are seen (see Fig. 4A.18 ). Mild nuclear pleomorphism and an occasional mitotic figure can be seen, but typically no marked increase occurs in mitotic activity, and atypical mitoses are not present. Necrosis is not usually found. The vascular channels range from capillary size to large sinusoidal spaces that may have a staghorn configuration. A characteristic but not pathognomonic feature is the presence of perivascular hyalinization (see Fig. 4A.18 ). The cellular proliferation may compress and obscure blood vessels of smaller size. Extravasated erythrocytes are often identified. An inflammatory component, usually including mast cells but also eosinophils, is present scattered throughout the tumor. Multinucleate (tumor) giant cells can be seen in a minority of cases. Fibrosis or a myxoid stroma may be seen, especially in tumors with degenerative change. Heterologous metaplastic elements, including bone and cartilage, may occasionally be seen.

Differential Diagnosis

The differential diagnosis includes LCH, angiofibroma, solitary fibrous tumor, smooth muscle tumors (leiomyoma and leiomyosarcoma), and synovial sarcoma. In contrast to solitary fibrous tumor, SG lacks the presence of ropey keloidal-appearing collagen or amianthoid fibers, diffuse and strong CD34, and STAT6 reactivity. Both tumor types show the presence of β-catenin (nuclear) staining.

Definition

Fibromatosis is a locally infiltrative or aggressive, nonmetastasizing, (myo)fibroblastic neoplasm. Synonyms include aggressive fibromatosis and extraabdominal desmoid, desmoid-type fibromatosis .

Clinical Features

Involvement of the head and neck region occurs primarily in the soft tissues of the neck. Excluding the neck, the common sites of occurrence are the sinonasal tract, nasopharynx, tongue, and oral cavity. From 10% to 15% of cases occur in the head and neck. In children, up to 30% of cases occur in the head and neck. In the sinonasal tract, the maxillary sinus is the most common site. Symptoms vary according to site. In the sinonasal tract and pharynx, the clinical presentation includes a painless enlarging mass or nasal obstruction. With progression of disease, other symptoms, including epistaxis, facial deformity, proptosis, and dysphagia, may occur.

Etiology

There is an association with Gardner syndrome (familial colorectal polyposis), including familial adenomatous polyposis. Gardner syndrome is characterized by the presence of intestinal polyposis, bone tumors (osteomas), and soft tissue tumors. Aside from fibromatoses, the soft tissue tumors include epidermoid cysts and lipomas. The majority of fibromatosis associated with Gardner syndrome occur intraabdominally.

Treatment and Prognosis

These lesions present difficulties in management because of insinuation of the lesion into adjacent structures without clear demarcation, making complete excision difficult. This may potentially predispose to reoccurrence, which usually occurs within the first few years after surgery. Radiotherapy has been used with some success in patients with residual tumor and/or recurrent disease. Hormonal therapy has been used with varying results. More recently, receptor tyrosine kinase inhibition as well as imatinib and sorafenib have been used with varying efficacy in treatment of primary and recurrent disease. Death due to uncontrolled local disease is an extraordinary occurrence. Spontaneous regression of the lesion may occur but is also rare. In extremely rare cases, transformation to an overt malignancy (fibrosarcoma) has been reported and likely relates to prior radiation therapy.

Pathology

The gross and histologic appearances are the same as those in fibromatoses at more common locations (see Chapter 24 ).

Differential Diagnosis

The differential diagnosis primarily includes reactive fibrosis and fibrosarcoma. In contrast to fibrosarcoma, fibromatoses lack a herringbone growth pattern, hypercellularity, and increased mitotic rate. Other differential diagnostic considerations include peripheral nerve sheath tumors, myxoma and fibromyxoma, solitary fibrous tumor, myofibromatosis, nodular fasciitis, fibroosseous lesions, and myofibroblastic tumors (inflammatory myofibroblastic tumor, low-grade myofibroblastic sarcoma).