Nonsquamous Lesions of the Nasal Cavity, Paranasal Sinuses, and Nasopharynx

Clinical Features

Rhinitis (inflammation of the nose), sinusitis (inflammation of the paranasal sinuses), and rhinosinusitis (inflammation of both) are the most common disorders of the sinonasal tract. There are numerous causes of rhinosinusitis, including allergies, infections, aspirin intolerance, exposures to toxins or medications, pregnancy, systemic diseases, and others. Acute rhinosinusitis is usually infectious, most commonly viral in etiology (e.g., adenoviruses, echoviruses, rhinoviruses, or others). Bacterial infection can be superimposed on viral rhinosinusitis, and is most commonly the result of Streptococcus pneumonia and Hemophilus influenza . Viral rhinosinusitis causes a watery nasal discharge, while bacterial disease causes a mucopurulent discharge, headache, and fever. Chronic rhinosinusitis (i.e., longer than 12 weeks) is most often allergic, resulting from an immunoglobulin (Ig)E-mediated reaction. Affected patients complain of a clear nasal discharge, sneezing, and itching after exposure to the offending allergen. Chronic allergic rhinitis plays a significant role in the genesis of inflammatory polyps, described later. Chronic sinusitis is also a component of Kartagener syndrome. This syndrome also includes bronchiectasis and situs inversus and is caused by a defective ciliary cytoskeleton lacking dynein arms. Occasionally, pathologists will be asked to perform assessment of nasal biopsies in cases suspicious of Kartagener syndrome. By imaging, inflamed sinuses demonstrate opacification and mucosal thickening; air-fluid levels are a classic finding in acute disease.

Pathologic Features

The gross findings of rhinosinusitis are nonspecific. Histologically, rhinosinusitis is characterized by a submucosal inflammatory infiltrate, generally composed of lymphocytes, plasma cells, macrophages, and eosinophils, which predominate in allergic disease. Acute rhinosinusitis is characterized by increased neutrophils, especially when bacterial in etiology. There is often a component of stromal edema which leads to the development of inflammatory polyps (described in detail later). The surface epithelium may demonstrate changes as well, including inflammation, squamous metaplasia, or reactive papillary hyperplasia (so-called papillary sinusitis).

Differential Diagnosis

The diagnosis of rhinosinusitis is usually straightforward. On rare occasions, squamous metaplasia and/or papillary hyperplasia can raise the possibility of a sinonasal papilloma.

Treatment and Prognosis

Acute viral rhinosinusitis is treated symptomatically, while bacterial disease requires antimicrobials. Chronic allergic sinusitis is treated with antihistamines, intranasal corticosteroids, and/or allergic desensitization. Patients with chronic rhinosinusitis refractory to medical therapy may require endoscopic surgery.

Clinical Features

Mucous impaction is an uncommon inflammatory lesion that has also been called inspissated mucus or snotoma . It is most commonly seen in children and young adults with a long-standing history of chronic rhinosinusitis of any etiology. It is a pseudoneoplastic process resulting from the impaction of a large amount of mucus within the maxillary antrum. This mucous mass produces opacification of the antrum, usually without sinus wall destruction or invasion. However, rare cases may present with pressure erosion and destruction of bone, similar to a mucocele.

Pathologic Features

Grossly, the mass has a translucent appearance and a gray to pink color. Microscopically, it consists of mucus containing numerous neutrophils, lymphocytes, and plasma cells admixed with desquamated respiratory-type epithelium.

Differential Diagnosis

The differential diagnosis of mucous impaction includes a maxillary bone myxoma, well-differentiated mucinous adenocarcinoma, and embryonal rhabdomyosarcoma. The typical clinical history, the lack of destruction or invasion of the maxillary bone, the presence of degenerating inflammatory cells, and the absence of neoplastic cells should argue against the diagnosis of a neoplasm.

Treatment and Prognosis

This is a pseudoneoplastic condition with an excellent prognosis. The treatment of choice is removal of the impacted mucus with treatment of the underlying inflammatory process. Rarely, laryngeal stridor may occur because of impacted nasal/nasopharyngeal mucous secretions in the larynx.

Clinical Features

Sinonasal inflammatory polyps are common, nonneoplastic masses of sinonasal tissue that essentially result from edema within the submucosa. Antrochoanal polyp is regarded as a subtype of inflammatory polyp.

Inflammatory polyps are most often seen in adults with a long-standing history of chronic rhinitis accompanied by allergy, asthma, aspirin intolerance, or diabetes mellitus. They are multiple and often present as bilateral masses arising from the lateral nasal wall. Symptoms at presentation include nasal obstruction, rhinorrhea, and headaches. Radiologic studies usually reveal a soft-tissue mass with air-fluid levels occupying the nasal cavity or paranasal sinuses. Large inflammatory polyps can be locally destructive, destroying bone and extending into the nasopharynx, orbit, and cranial cavity. Inflammatory nasal polyps develop in approximately 20% of children with cystic fibrosis, and in some, they may be the initial clinical manifestation of the disease. Children with inflammatory nasal polyps should be investigated for cystic fibrosis.

Antrochoanal polyps are usually seen in younger patients (teenagers and young adults), usually males, and are typically unilateral. These lesions arise in the maxillary antrum and extend secondarily into the nasal cavity from the nasal choana.

Pathologic Features

Inflammatory polyps can measure up to several centimeters in diameter and have a translucent, myxoid or gelatinous appearance. Histologically, the most prominent feature is an edematous stroma, which contains a mixed inflammatory infiltrate composed of eosinophils, lymphocytes, and plasma cells ( Fig. 3.1A ). They are lined with respiratory epithelium with an often hyalinized basement membrane ( Fig. 3.1B ). The epithelium may exhibit squamous metaplasia, and in some cases, this metaplastic epithelium shows a degree of reactive atypia suggestive of dysplasia ( Fig. 3.2 ). Sometimes Charcot-Leyden crystals associated with abundant eosinophils may be seen. The stroma contains a variable number of stellate or spindled fibroblasts, some of which may exhibit enlarged, hyperchromatic nuclei ( Fig. 3.3A ). Typically, inflammatory polyps contain relatively few seromucinous glands. Larger inflammatory polyps may demonstrate prominent submucosal hemorrhage with fibrin deposition or infarction with vascular organization, a pattern that has been referred to as angiomatous or angiectatic ( Fig. 3.3B ). Additional secondary changes include surface ulceration, fibrosis, infarction, granulation tissue, cartilaginous or osseous metaplasia, glandular hyperplasia, and, sometimes, granuloma formation. Polyps associated with cystic fibrosis are dominated by dilated glands with inspissated mucin, contain fewer eosinophils and lack the basement membrane thickening and submucosal hyalinization seen in conventional inflammatory polyps ( Fig. 3.4 ).

Antrochoanal polyps grossly exhibit a long fibrous stalk ( Fig. 3.5A ). Histologically, they tend to be more fibrotic and less edematous and have fewer eosinophils than usual inflammatory polyps. Moreover, antrochoanal polyps tend to lack a hyalinized basement membrane ( Fig. 3.5B ).

Differential Diagnosis

The diagnosis of sinonasal inflammatory polyp is usually straightforward. In some inflammatory polyps, the number of atypical, degenerative fibroblasts (see Fig. 3.3A ) is sufficient to raise the possibility of a malignant tumor, particularly embryonal rhabdomyosarcoma. The typical clinical history and the presence of a heavy inflammatory infiltrate point toward inflammatory polyp. Moreover, the atypical stromal cells of benign polyps are singly and randomly distributed, do not aggregate (e.g., no “cambium” layer characteristic of embryonal rhadomyosarcoma), are not mitotically active, and are negative for desmin and myogenin.

Other lesions that should be separated from sinonasal polyps are nasopharyngeal angiofibroma and sinonasal papilloma. Nasopharyngeal angiofibroma contains stromal myofibroblasts with a spindle or stellate shape admixed with thick abnormal vessels not seen in polyps. Nasal polyps also lack the thick fibrovascular papillary cores, the inverted growth pattern, and the intraepithelial microcysts of sinonasal papillomas. However, early inverted papillomas may occasionally involve a nasal polyp.

Treatment and Prognosis

The treatment of sinonasal polyps is surgical resection. Identification and treatment of etiologic factors are necessary to prevent recurrences. Antrochoanal polyps may also recur if the stalk is not completely resected.

Clinical and Pathologic Features

Leprosy is a slowly progressive disease caused by Mycobacterium leprae . The infection affects the skin and peripheral nerves and results in disabling deformities. This infection has largely disappeared in the Western world but still affects millions of people in underdeveloped countries. Leprosy is a disease with clinicopathologic manifestations determined by the host’s cellular immune response. Two clinical forms of the disease occur, depending on whether the host is capable of mounting a T cell–mediated immune response or is anergic. Those with an immune response develop tuberculoid leprosy. Anergy results in lepromatous leprosy.

M. leprae is transmitted from person to person via aerosols that originated from lesions in the upper respiratory tract. The vast majority of the lesions observed in the nasal cavity are of the lepromatous type and consist of large numbers of macrophages filled with massive quantities of acid-fast bacilli. Fibroblasts, neutrophils, eosinophils, and plasma cells can also be present. Occasionally, some of these cells are seen along nerves that show Schwann cells containing large numbers of bacilli. The bacilli may also be found within endothelial cells and fibroblasts, mucous glands and ducts, and vascular lumens. The bacilli are highlighted with the Fite-Faraco modification of the Ziehl-Nielsen stain.

Differential Diagnosis

The main differential diagnosis of tuberculoid leprosy includes sarcoidosis, tuberculosis, certain fungal infections, and GPA. All these latter entities have significantly different epidemiologic findings, clinical manifestations, and serologic and microbiological tests that should allow their distinction from tuberculoid leprosy. Rhinoscleroma may resemble lepromatous leprosy, but in leprosy, the Fite stain should demonstrate the presence of large numbers of acid-fast organisms.

Treatment and Prognosis

Leprosy is treated with multiagent antimicrobial therapy. Adequate treatment requires the use of most of these drugs for several years. Supportive care is also important in reducing morbidity and injuries leading to blindness and mutilation. The prognosis depends on clinical stage of the disease, type of disease, availability of effective drugs, adherence to treatment, and supportive care measures.

Clinical Features

Rhinoscleroma is a chronic granulomatous disease that is uncommon in North America but endemic in parts of Central and South America, North and Central Africa, and certain areas of Eastern Europe. Rhinoscleroma is caused by the gram-negative rod Klebsiella rhinoscleromatis and affects primarily the nasal cavity and nasopharynx. Involvement of the lip, oropharynx, and palate may also be seen. In severe cases, the infection causes bone destruction and nasal obstruction with extension into the paranasal sinuses, orbit, middle ear, larynx, and tracheobronchial tree. Clinically, rhinoscleroma is characterized by three phases: rhinitic, florid, and fibrotic. The initial symptoms resemble a common cold, but in the fully developed disease, there are also dysphonia, aphonia, and anosmia. Clinically, anesthesia of the soft palate and hypertrophy of the uvula should suggest the diagnosis of rhinoscleroma. In advanced cases, the destruction of the nasal cartilage, with the formation of nodules, causes a severe deformity referred to as Hebra nose .

Pathologic Features

Pathologically, rhinoscleroma is also characterized by three phases: rhinitis or catarrhal, florid or granulomatous, and fibrotic. In the catarrhal phase, the tissue changes are nonspecific and consist of abundant neutrophils, cellular debris, and granulation tissue. In the granulomatous phase, rhinoscleroma is characterized by pseudoepitheliomatous hyperplasia of the overlying mucosa and a dense chronic inflammatory infiltrate composed of lymphocytes, plasma cells with numerous Russell bodies, and large macrophages with clear vacuolated cytoplasm. These macrophages are referred to as Mikülicz cells ( Fig. 3.7 ). The microorganisms are present within the cytoplasm of these macrophages and can be demonstrated by a Warthin-Starry silver stain (see Fig. 3.7 inset), a Giemsa stain, or a Gram stain. In inconclusive cases, the bacteria can be identified in 1- to 2 mm-thick sections, stained with toluidine blue. In the final fibrotic phase, there are variable degrees of fibrosis and the Mikülicz cells are absent or are difficult to identify.

Differential Diagnosis

The differential diagnosis of rhinoscleroma includes leprosy, sarcoidosis, tuberculosis, fungal infections, and sinonasal sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease). Clinicopathologic features, special stains, and microbiologic cultures are helpful in excluding other granulomatous infections. In leprosy, the organisms are acid fast and can be demonstrated by the Fite stain. Rhinoscleroma lacks the large atypical cells with emperipolesis that show positive S100 protein immunostaining seen in sinus histiocytosis with massive lymphadenopathy.

Treatment and Prognosis

Long-term systemic antibiotics are indicated for rhinoscleroma. Surgery and laser ablation of tissue deformities caused by fibrous masses in the late fibrous phase of rhinoscleroma may be considered to correct stenotic nasal passages. However, these corrective procedures can only be used after the patient is clinically and histologically free of disease, and cultures have been negative.

Clinical Features

Sinonasal fungal disease can be clinically separated into noninvasive (allergic fungal sinusitis and mycetoma) and invasive (acute/fulminant and chronic) forms. Occasionally, the histologic distinction between invasive and noninvasive fungal disease is difficult and the distinction needs to be made on clinical and radiologic grounds.

Allergic fungal sinusitis is a noninvasive fungal pansinusitis that occurs in immunocompetent individuals, with a long-standing history of atopy, elevated levels of total immunoglobulin E, and peripheral eosinophilia. Initially, this condition was attributed to infection with Aspergillus spp. because of the presence of dichotomous fungal hyphae and the histologic similarities to allergic bronchopulmonary aspergillosis. Subsequent studies, however, have demonstrated that nearly 80% of cases of allergic fungal sinusitis are caused by members of the Dematiaceae family, with the most common genus being Bipolaris followed by Curvularia, Exerohilum, Alternaria , and Cladosporium .

Mycetoma (fungus ball) results from colonization of the paranasal sinuses (especially maxillary) by fungal organisms (most frequently Aspergillus species). Patients complain of nasal discharge and allergic symptoms, similar to allergic sinusitis, and radiologic studies reveal sinus opacification, sometimes with calcifications.

Acute fulminant or angioinvasive fungal infections are common in immunocompromised hosts, particularly those with HIV infection, uncontrolled diabetes mellitus, and hematologic malignancies. It is an aggressive infection that can quickly extend into soft tissues, orbit, and brain. Acute fungal sinusitis is often caused by Mucor species. Other fungi capable of causing invasive fungal sinusitis include Aspergillus , Candida spp., cryptococcosis, Curvularia lunata , Pseudallescheria boydii , and Fusarium spp.

Chronic invasive fungal sinusitis is associated with partial immunodeficiency, for example diabetes mellitus or chronic corticosteroid therapy. Patients complain of chronic headaches or facial swelling over a period of months or even years. Aspergillus fumigatus is the most common infectious agent.

Pathologic Features

Histologically, allergic fungal sinusitis consists of abundant pale eosinophilic or basophilic allergic mucin with a laminated, “tigroid” appearance ( Fig. 3.9A ). The mucin contains numerous eosinophils, plasma cells, and lymphocytes admixed with cellular debris, sloughed respiratory epithelial cells, and edematous respiratory mucosa. Charcot-Leyden crystals with clusters of degenerated eosinophils are constant microscopic features. Degenerating, distorted fungal hyphae are identified with GMS stain (see Fig. 3.9A inset). No fungal balls or invasion of bone or mucosa is present. Because of morphologic similarities of the fungi causing allergic fungal sinusitis, cultures are mandatory for the determination of the exact organism responsible.

Mycetoma consists histologically of a matted collection of distorted fungal hyphae, sometimes demonstrating calcifications ( Fig. 3.9B ). There is no invasion of tissue by fungal elements. Unlike in other forms of fungal sinus disease, fruiting bodies (conidia) may be evident in mycetomas (see Fig. 3.9B inset). Mycetomas caused by Aspergillus niger specifically are unique, exhibiting hyphal pigmentation and calcium oxalate crystal deposition.

Chronic invasive fungal sinusitis is histologically characterized by fungal hyphae within tissue, with prominent granulomatous and chronic inflammation ( Fig. 3.9C ). The fungal organisms are readily identified by silver staining but often are not numerous. They have the thin, acute-angle branching typical of Aspergillus spp. (see Fig. 3.9C inset). In contrast to acute fungal sinusitis, necrosis and angioinvasion are not seen.

Acute fungal infections are characterized by acute inflammation, tissue necrosis, and numerous hyphae invading blood vessels ( Fig. 3.9D ). The degree of inflammation is often sparse, and out of proportion to the extent of fungal infestation. Recognition of Mucor is based on the identification of broad, ribbon-like pauciseptate hyphae (see Fig. 3.9D inset).

Differential Diagnosis

The differential diagnosis of fungal infections in the sinonasal tract includes a large number of nonneoplastic and neoplastic diseases. Sinonasal tuberculosis is generally accompanied by pulmonary disease and a positive skin test. Microscopically, there are large numbers of granulomas with caseous necrosis that are not typically seen in fungal infections. GMS and acid-fast stains are helpful in revealing the responsible organism. GPA may be difficult to exclude based on morphologic grounds alone because vasculitis may be a focal finding in nasal biopsies. However, most patients with GPA also have renal manifestations and serologic cytoplasmic antineutrophilic and myeloperoxidase antibodies. Sinonasal natural killer (NK)/T cell lymphomas may present with extensive tissue destruction with a polymorphous infiltrate involving the sinonasal tract. They also reveal the presence of an atypical lymphoid infiltrate not seen in sinonasal mycotic infections.

Treatment and Prognosis

The treatment and prognosis of sinonasal fungal disease varies depending on the type of infection, causative organisms, and underlying medical conditions. The treatment of most noninvasive fungal disease usually consists of sinusotomy and curettage of all necrotic and diseased tissue. The invasive forms, especially opportunistic mycosis associated with diabetes mellitus or immunosuppression, require radical surgical debridement and intravenous antifungal therapy. In those affected by mucormycosis, surgery has an important role in removing devitalized tissues because the vascular thrombosis present in necrotic tissues interferes with the delivery of antifungal agents. The treatment of allergic fungal sinusitis varies according to clinical features and extent of disease.

The prognosis of noninvasive fungal infections in the sinonasal tract is excellent. The invasive forms have a guarded prognosis. In the case of mucormycosis, the most important determinant of survival is the underlying disorder. Patients with no underlying disease had a survival rate of approximately 75%, whereas those with leukemia or renal disease had a survival rate of 20%. Adequate chemotherapy is also important in patient outcome; for example, the introduction of amphotericin B in the management of diabetic patients, with mucormycosis, increased the survival rate from 37% to 79%.

Clinical Features

Sinus histiocytosis with massive lymphadenopathy (SHML) is a rare proliferative disorder of histiocytes that presents primarily with marked enlargement of cervical lymph nodes; however, extranodal disease with involvement of the nasal cavity, orbit, and other head and neck sites is common. The mean age at onset is approximately 20 years, and immune dysregulation and viral infections may play a role in its development. Involvement of the sinonasal tract is often accompanied by nodal disease or extranodal lesions in other head and neck sites, though in approximately 20% of cases of sinonasal SHML, the upper aerodigestive passages are the only sites of disease. Laboratory manifestations include anemia, red-cell autoantibodies, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. While SHML was long believed to be a reactive condition, emerging evidence demonstrating oncogenic KRAS or MAP2K1 mutations in a subset of cases suggests that it may actually be neoplastic in nature.

Pathologic Features

Sinonasal SHML presents as nasal polyps or nodules with partial obstruction of the nasal cavity and is histologically characterized by a diffuse inflammatory infiltrate ( Fig. 3.10A ). The inflammatory cells consist of a polymorphic infiltrate composed of numerous plasma cells, often with abundant Russell bodies, small lymphocytes, polymorphs, eosinophils, and characteristic histiocytes with large vesicular nuclei, sometimes showing mild pleomorphism and small but distinct nucleoli ( Fig. 3.10B ). The cytoplasm of these histiocytes is abundant and clear or eosinophilic and often contains numerous intact lymphocytes, many of them within vacuoles. This phenomenon is known as emperipolesis . Fibrosis can be a prominent finding in extranodal disease and may hamper the recognition of the characteristic histiocytes of SHML. Lymphoid aggregates resembling a lymph node are also commonly seen in the nasal mucosa. S100 protein (see Fig. 3.10B inset), CD68, and CD163 antibodies are expressed by these cells.

Differential Diagnosis

The differential diagnosis of SHML includes rhinoscleroma, leprosy, Langerhans cell histiocytosis, and non-Hodgkin lymphoma (NHL). Separation of SHML from these entities is based on recognition of its characteristic morphologic features and the immunohistochemical profile of the histiocytes. The S100 protein–positive, atypical, large histiocytes, showing emperipolesis, are the hallmark of SHML and are absent in rhinoscleroma, leprosy, and NHL. The foamy histiocytes of rhinoscleroma contain gram-negative rods consistent with Klebsiella rhinoscleroma, while histiocytes in leprosy may show cytoplasmic acid-fast bacilli. Langerhans cell granulomatosis is a clonal proliferation of neoplastic histiocytes that express S100 protein, but also CD1a and langerin, in contrast to SHML.

Treatment and Prognosis

There is no consensus on treatment guidelines for sinonasal SHML. SHML is usually self-limiting, and as a result, surgery is generally reserved for symptomatic relief of compressive lesions.

Clinical Features

GPA (formerly known as Wegener granulomatosis) is a systemic vasculitis and necrotizing granulomatosis with involvement of the upper and lower respiratory tracts and kidneys. GPA was one of many lesions (including NK/T cell lymphoma, sarcoidosis, various infectious processes, etc.) previously included under the vague clinical terms of midfacial necrotizing lesion and lethal midline granuloma . The etiology of GPA remains unknown.

Clinically, patients with involvement of the upper respiratory tract usually present with sinusitis, rhinorrhea, headache, nasal obstruction, anosmia, sinus pain, and, less often, otitis media and mastoiditis caused by involvement of the eustachian tube. In most patients, there are also pulmonary or renal manifestations. Classic or cytoplasmic antineutrophilic cytoplasmic antibodies (c-ANCAs), directed against neutrophilic proteinase 3, are present in the serum of most patients; a minority have antibodies against myeloperoxidase or (peri)nuclear ANCAs, whereas others lack these antibodies altogether. The presence of these antibodies and their titers appear to be related to levels of disease activity.

Pathologic Features

The classic histologic triad of GPA is: (1) tissue necrosis, (2) granulomatous inflammation, and (3) vasculitis. In practice, the biopsy diagnosis of GPA of the sinonasal tract is frequently difficult and often inconclusive. This histologic appearance of GPA is often dominated by mixed acute and chronic inflammation, aggregating in small clusters and microabscesses. This intense inflammatory reaction may mask the key diagnostic features.

Coagulative necrosis is invariably present in GPA, but its detection in head and neck biopsy specimens depends on tissue sampling and biopsy sample size. The necrosis in GPA has a smudgy, basophilic quality because of the presence of granular cellular debris; this pattern is referred to as bionecrosis or collagenolytic necrosis ( Fig. 3.11A ). Usually, it is patchy in distribution and may have a “geographical” appearance, with a prominent rim of palisaded epithelioid and spindle-shaped macrophages. Giant cells are also often present around the necrotic areas.

The granulomas in GPA are poorly formed, and most often consist of loose aggregates of mononuclear and multinucleated macrophages ( Fig. 3.11B ), or more often, scattered isolated giant cells. The giant cells and granulomas can be found within the vessel wall, adjacent to the vessel, or distant from the affected vessels.

The necrotizing vasculitis involves arterioles and small arteries and veins. All stages of vasculitis may be present, ranging from acute to granulomatous to healed. The acute stage is characterized by patchy fibrinoid necrosis of the vessel wall accompanied by a prominent neutrophilic infiltrate. The inflammation and necrosis may involve part or the entire circumference of the affected vessel ( Fig. 3.11C ). Extravasated red blood cells, fibrin thrombi, and swollen endothelial cells are often seen. Multinucleated giant cells and histiocytes are present in granulomatous vasculitis. Healed vasculitis is characterized by concentric fibrosis surrounding an endothelium-lined vascular lumen. Frequently, recognition of involved blood vessels is difficult; in these instances, the use of elastic stains is helpful to identify the fragmented elastic remnants.

The utility of head and neck biopsies in establishing the diagnosis of GPA depends on a constellation of clinical and histopathologic findings. Because it is rare for all histologic features of GPA to be present in a single biopsy, many biopsies are often needed to establish a diagnosis. In general, the diagnosis of GPA requires a careful correlation of clinical, serologic, microbiologic, and pathologic data.

Differential Diagnosis

The differential diagnosis of GPA includes infectious processes, Churg-Strauss syndrome, and sinonasal lymphoma. The diagnosis of aggressive sinonasal infections resides in close clinicopathologic correlation and the identification of an infectious agent in microbiologic cultures or biopsy material. Sinonasal infections generally do not have concurrent pulmonary and renal involvement and lack serum ANCAs. Although the mucosa of the oral cavity, sinonasal tract, and nasopharynx can be inflamed and ulcerated, it is rare to find the extensive cartilage and bone destruction associated with sinonasal lymphoma. Sinonasal lymphoma should not have pulmonary or renal disease and also lacks perinuclear ANCAs. In difficult cases, immunophenotyping and potentially molecular pathology studies should be used to exclude the diagnosis of lymphoma.

Treatment and Prognosis

The prognosis of patients with GPA largely depends on the extent of the disease and the treatment used. Patients with the limited form of the disease may have only nasal and pulmonary involvement, without glomerulonephritis or systemic involvement. The use of corticosteroids and immunosuppressive agents has greatly reduced the mortality of GPA, with 10-year survival rates now exceeding 80%.

Clinical Features

Eosinophilic angiocentric fibrosis (EAF) of the sinonasal tract is an exceedingly rare condition characterized by progressive, submucosal perivascular fibrosis of unknown etiology. Cases have been associated with granuloma faciale or, rarely, GPA. EAF predominantly affects women, with a female-to-male ratio of 4:1. Age at presentation has ranged from 19 to 79 years, with a mean age of 50 years. Most patients present with a history of long-standing and progressive nasal obstruction, accompanied by discharge. Pain and epistaxis have been reported. Physical examination reveals mucosal thickening or a mass with narrowing of the nasal passages. The septum and lateral nasal wall are most commonly affected, but involvement of the maxillary sinus, facial or orbital soft tissues, or subglottis can be seen. Recent evidence suggests that EAF may fall within the spectrum of IgG4-related fibroinflammatory disorders.

Pathologic Features

Morphologically, EAF is characterized by a variable and evolving mixture of a rich polymorphic cellular inflammatory infiltrate, nonnecrotizing eosinophilic vasculitis, and fibrosis. The eosinophilic vasculitis affects submucosal capillaries and venules. The inflammatory infiltrate is composed of numerous eosinophils, with variable numbers of B and T lymphocytes, plasma cells, neutrophils, and macrophages. The fibrosis consists of a distinctive perivascular concentric fibrosis with an “onion-skin” appearance ( Fig. 3.12 ). In later stages of the disease, whorls of collagen and reticulin fibers are seen. Typically, the inflammatory infiltrate and the vasculitis become sparser as the fibrosis increases in density. Recent papers have described an increased number of IgG4-positive plasma cells in cases of EAF.

Differential Diagnosis

The differential diagnosis of sinonasal EAF includes GPA, Churg-Strauss syndrome, granuloma faciale, and infection. Perivascular fibrosis is not a typical finding in GPA; furthermore, giant cells, necrosis, and increased serum ANCAs are not seen in EAF. Churg-Strauss syndrome has fibrinoid necrosis and granulomas that are absent in EAF. Granuloma faciale is almost always seen in the face, more commonly affects males, and exhibits prominent vasculitis without concentric perivascular fibrosis. Mucosal ulceration, geographic or fibrinoid necrosis, thrombosis, giant cells, and granulomas are not microscopic features of EAF.

Treatment and Prognosis

Surgical resection with relief of the nasal obstruction is the treatment of choice in EAF, although recurrences are extremely common and multiple excisions are frequently required. The efficacy of steroids and cytotoxic drugs in the management of EAF remains largely unknown.

Clinical Features

Paranasal mucoceles are chronic, nonneoplastic cystic lesions secondary to obstruction of the sinus outlet. They occur more frequently in the ethmoid sinuses and frontal sinus region (90%) and less commonly in the maxillary and sphenoid regions. In most instances, the blockage is secondary to an inflammatory or allergic process, although cystic fibrosis, trauma, or neoplastic processes have also been implicated. The symptoms associated with these lesions vary depending on the location, size, and degree of extension into adjacent structures and include facial pain and swelling, proptosis, rhinorrhea, and nasal obstruction. Radiologically, there is opacification of the affected sinus; in long-standing cases, erosion with destruction or sclerosis of the adjacent bone can also be present ( Fig. 3.13A )

Pathologic Features

The gross appearance is characterized by a cyst filled with a mucoid or gelatinous secretion. Microscopically, the cysts are lined with unremarkable, attenuated pseudostratified ciliated columnar epithelium, variably accompanied by secondary changes such as fibrosis, granulation tissue, and recent and remote hemorrhage with cholesterol granulomas ( Fig. 3.13B ). In some instances, the epithelium exhibits foci of squamous metaplasia. Sinus mucoceles have been divided into two groups: internal and external types. In the internal type, the cyst herniates into the submucosal tissues of the bony wall of the sinuses, whereas in the external type, the cyst extends into the cranial cavity or subcutaneous tissues.

Differential Diagnosis

The clinical and radiologic presentation can closely simulate those of a neoplasm, but the histologic findings are nonspecific and often resemble normal tissue. The pathologic diagnosis of sinus mucocele should be closely correlated with the clinical history and radiologic and surgical findings. The characteristic clinical and radiologic findings and the absence of tumor cells in pathologic material should exclude the possibility of a neoplasm.

Treatment and Prognosis

The treatment of mucocele consists of surgical relief of the sinus obstruction and decompression of the mucocele. This may be accomplished by endoscopic surgery or by removal of the medial maxillary wall.

Clinical Features

Respiratory epithelial adenomatoid hamartoma (REAH) is a rare lesion characterized by an adenomatoid proliferation of respiratory ciliated cells occurring in the nasal cavity, sinuses, and nasopharynx.

This glandular process is derived from the Schneiderian or surface sinonasal epithelium, not from seromucinous glands. Most patients are males in the fifth or sixth decade of life. In the study by Wenig and Heffner, there were 27 males and four females with a median age of 58 years. The symptoms at presentation are nonspecific and include rhinosinusitis, allergies, nasal obstruction, stuffiness, septum deviation, and epistaxis. At physical examination, the lesion appears as a polypoid mass most commonly arising in the posterior septum. Involvement of the lateral wall, middle meatus, and inferior turbinate is less common.

Pathologic Features

Under low-power examination, these lesions have a polypoid appearance. They are characterized by a proliferation of invaginated glands of ciliated surface respiratory epithelium, surrounded by a thick, eosinophilic, hyalinized basement membrane ( Fig. 3.14A ). The glands are round or oval and vary in size from small to large with a dilated appearance, often exhibiting mucinous metaplasia. The glandular lumina contains mucinous or amorphous material. The stroma surrounding glands is often edematous and contains a mixed inflammatory infiltrate resembling the stroma of inflammatory polyps. Infrequently, the larger glands may be intermixed with bland, smaller, uniform glands, resembling those seen in seromucinous hamartoma (described later) (see Fig. 3.14B ).

Immunohistochemically, REAH is positive for cytokeratins, including CK7, but not for CK20 and CDX2. Myoepithelial/basal cell markers are positive in most cases, but their absence does not support a diagnosis of adenocarcinoma.

It is still debated whether these proliferations represent a reactive process, a hamartoma or a benign neoplasm (adenoma). The rate of fractional allelic losses observed by Ozolek et al. that are intermediate between inflamed mucosa and sinonasal adenocarcinoma supports the hypothesis that it may represent a benign neoplasm.

Differential Diagnosis

The most important differential diagnosis is a well-differentiated adenocarcinoma. REAH does not have the complex glandular growth with a back-to-back and/or cribriform pattern and lacks the infiltrative growth and desmoplastic stroma of well-differentiated adenocarcinomas. Sinonasal adenocarcinomas exhibit aggressive growth with invasion of bone and soft tissues, which is not seen in REAH. However, some examples of sinonasal low-grade adenocarcinomas have been reported to be associated with REAH.

These lesions may also be misdiagnosed as inverted sinonasal papilloma. However, respiratory hamartomas are not lined with squamous or cylindrical epithelium, with intraepithelial mucous cysts, as is the case with papillomas.

Treatment and Prognosis

REAH is a benign condition with no risk of recurrence, persistence, or progression. The treatment should be conservative local excision or polypectomy.

Clinical Features

Seromucinous hamartoma (SH) is a benign overgrowth of seromucinous glands of the nasal cavity. Similarly to REAH, SH involves more frequently the posterior nasal septum and the nasopharynx, but they have also been described in the lateral nasal wall. They are rare lesions that present as polypoid masses over a wide age range (mean 56 years) and a slight male predominance (3:2). Presenting symptoms are nonspecific and include obstruction and epistaxis.