I. NORMAL ANATOMY
A. Nasal cavity. The normal sinonasal region consists of the central nasal cavity, paired bilateral paranasal sinuses, and the nasopharynx. The nasal cavity consists anteriorly of the nasal vestibule, the small hair-bearing region just inside the nasal ostia, with the remainder representing the nasal antrum; the nasal cavity has four walls, a central dividing septum, and paired upper, middle, and lower turbinates. The nasal vestibule lining is an extension of the surrounding facial skin, and as such has a stratified, keratinizing squamous epithelium with associated dermal appendages and hair. It extends for 1 to 2 cm into the nasal cavity. The nasal antrum is lined by pseudostratified ciliated columnar (respiratory-type) epithelium of ectodermal origin referred to as the Schneiderian membrane (e-Fig. 3.1).* The submucosa consists of minor salivary gland mucoserous glands embedded in fibrovascular connective tissue with small ducts that convey their secretions to the surface. The turbinates have a more richly vascular stroma. The roof of the nasal cavity contains the cribriform plate with olfactory mucosa, a modified respiratory-type epithelium with olfactory nerve cells, and supporting cells.
B. Paranasal sinuses. The paranasal sinuses consist of the maxillary (largest), frontal, sphenoid, and ethmoid sinuses. They drain into the nasal cavity and are air filled, intraosseous, and open. The ethmoid sinuses are small and complex (referred to as the ethmoid labyrinth or air cells). All paranasal sinuses are in continuity with the nasal cavity so they have a similar, although thinner, mucosa. The submucosa is also thinner, looser, and less vascular than in the nasal cavity, although it does contain prominent seromucinous glands.
C. Nasopharynx. The nasopharynx is the most cephalad portion of the pharynx and is a cuboidal structure. Its roof is formed by the pharyngeal tonsil. The lateral walls are the most pathologically important because they contain the openings of the Eustachian tubes, and a depression posterior to the torus tubarius called the fossa of Rosenmüller. The fossa of Rosenmüller is the most common site of origin for nasopharyngeal carcinoma (NPC). Since the nasopharynx is surrounded by bone and vital structures, it is poorly accessible for surgery. The epithelial lining consists of a mixture of stratified squamous, intermediate (or transitional), and respiratory-type epithelium.
II. GROSS EXAMINATION, TISSUE SAMPLING, AND HISTOLOGIC SLIDE PREPARATION
A. Endoscopic biopsies. Most of the specimens from this region consist of endoscopic forcep biopsies. The small tissue pieces should be placed immediately into 10% buffered formalin or other appropriate fixative. If there is a suspicion of lymphoma, a minimum of three biopsy passes should be submitted in saline or RPMI medium and send directly for an appropriate hematopathology workup. Standard formalin-fixed specimens should undergo gross examination and description documenting the exact number of pieces present, and then should
be entirely submitted for histologic examination (three hematoxylin and eosin [H&E] levels cut per block). For very small specimens, or where few pieces are obtained from clinical masses, it is strongly recommended that additional unstained slides be cut from the block on initial submission for potential use for immunohistochemistry or special stains.
B. Functional endoscopic sinus surgery (FESS; “sinus contents”). The tissue consists of fragments of ethmoid and maxillary ostium sinus bone and mucosa, resected inflammatory polyps, and nasal cavity and sinus tissue obtained by suction devices. These samples should be described, measured, and submitted for histologic examination. If firm or dense tissue fragments are identified, they should be submitted as they may represent an unsuspected neoplasm. Otherwise, pieces of intact tissue should be collected from the blood and fluid from the suction device, inspected grossly, and measured in aggregate. Only one cassette of these fragments need be submitted for histologic examination with decalcification in EDTA or formic acid if gross pieces of bone are identified.
C. Resections. Surgical resections for sinonasal tumors are complex and varied, and are guided by tumor location, extent, and type. They always consist of soft tissue, mucosa, and bone. Margins are in large part guided by the separate specimens submitted for frozen section. The main specimen should be oriented, the tumor identified, and mucosal, soft tissue, and bone margins identified. The main specimen should be described and measured; the soft tissue margins are inked and then mucosal and soft tissue margin sections sampled. If the tumor is relatively distant from a margin, 1 to 2 mm thick shave sections are preferred; if the tumor approximates a margin (within 1 to 2 mm), radial sections are taken. After this, the tumor is sectioned and sampled. Four to five sections should be taken from tumors, or if small, tumors should be entirely submitted for histologic examination. Often sectioning requires a saw to cut through bone to demonstrate the relationship of the lesion to the adjacent structures. The bone should be decalcified, and shave sections from the bone margins as well as sections demonstrating tumor involving bone should be taken.
D. Frozen sections are a critical element of surgical therapy for head and neck tumors. Although practices vary, most institutions have margins taken as small pieces by the surgeon from the periphery of the surgical defect after the tumor has been removed. The pieces should be evaluated grossly for mucosa (which is typically shiny and pink-tan on one surface of the tissue); if present, the tissue should be oriented to demonstrate this mucosal surface on one edge of the section. Two (or at our institution, three) high quality sections are obtained with the second and third levels taken deep into the tissue to ensure adequate sampling.
The tissue that remains after a frozen section should be submitted for evaluation on permanent sections. This is done to further assure adequate sampling of the tissue and to help resolve a number of issues from frozen section including freezing and cautery artifact, amount of tumor represented, and orientation/embedding issues. The final margin status is therefore a conglomerate of the frozen section slides, permanent slides of the frozen tissue, and the margins of the resection specimen itself.
III. DIAGNOSTIC FEATURES OF COMMON DISEASES
A. Inflammation and infection. These processes are extremely common in the United States, necessitating a large amount of medical care and surgery.
1. Acute rhinosinusitis. Acute sinusitis is rarely seen by the pathologist because it is treated medically. However, typical histologic findings include neutrophils migrating through, and present in, the respiratory-type mucosa with luminal contents showing necrotic material, apoptotic neutrophil nuclear debris, and mucin with abundant neutrophils.
2. Chronic rhinosinusitis. Chronic inflammation of the nasal cavity can result from allergy, upper respiratory tract infection, or cystic fibrosis. Sinusitis is
thought to occur secondary to obstruction of the outflow of the paranasal sinuses by myriad etiologies such as edema and inflammation, or anatomic abnormalities, particularly in children. Some of the most common obstructing agents are inflammatory polyps, a deviated septum, or concha bullosa (air pocket in the middle turbinate). Finally, rare genetic conditions such as immotile cilia syndrome (Kartagener’s syndrome) cause chronic sinusitis. Complications include secondary bacterial infection and, in chronic allergic sinusitis, the development of inflammatory polyps.
Specimens from FESS in chronic sinusitis typically show edema of the submucosa with a mixture of lymphocytes, plasma cells, and eosinophils, the latter sometimes being quite prominent. The abundance and distribution of eosinophils histologically do not have a clinical correlate other than suggesting allergy as an underlying etiology for the sinusitis.
3. Wegener granulomatosis is an autoimmune disorder characterized by necrotizing vasculitis that affects the nasal cavity and paranasal sinuses, pulmonary, and/or renal systems. Manifestations of nasal cavity/paranasal sinus involvement include rhinorrhea, sinusitis, headache, nasal obstruction, anosmia, and sometimes middle ear and mastoid symptoms if inflammation obstructs the Eustachian tube.
Histologically, in biopsies of the sinonasal region, the diagnosis can be quite difficult. Features include mucosal ulceration, acute and chronic inflammation, necrosis, and granulomas. Wegener granulomatosis causes a vasculitis which is often obscured by the inflammation, so elastic stains such as Verhoeff-van Gieson may be helpful to demonstrate the elastic fibers of inflamed vessels. The vasculitis involves arterioles, small arteries, and veins with changes ranging from fibrinoid necrosis with neutrophils and associated extravasated red blood cells and fibrin thrombi, to granulomatous inflammation with multinucleated giant cells and histiocytes (e-Fig. 3.2). It is very important to correlate the histologic findings with clinical information and laboratory investigation, which reveals cytoplasmic antineutrophil antibodies (cANCA) in approximately 90% of patients.
4. Inflammatory polyps. Sinonasal inflammatory polyps are nonneoplastic mucosal and submucosal projections that arise in longstanding chronic rhinitis, usually associated with allergy or asthma. They are seen most commonly in adults but can be seen in children as well, particularly in those with cystic fibrosis. Symptoms include headache, nasal obstruction, and rhinorrhea. They are multiple, often bilateral, and most commonly arise from the lateral nasal wall. Although nonneoplastic, they are capable of dramatic behavior including deviation of the septum, destruction of bone, and extension into the nasopharynx and rarely the orbit or cranial cavities.
Grossly, inflammatory polyps can measure up to several centimeters and are boggy, gelatinous, and partially translucent with broad bases. Microscopically, there is a highly edematous or lightly myxoid stroma with a mixed inflammatory infiltrate of lymphocytes, plasma cells, and a variable number of eosinophils. There are few small vessels and minimal, bland, spindled stromal cells. Inflammatory polyps typically are devoid of seromucinous glands, a feature that is particularly helpful in identifying them when they are in fragmented pieces (e-Fig. 3.3). The surface mucosa is typically intact and lined by respiratory epithelium with a variably thickened basement membrane, although it occasionally shows squamous metaplasia.
5. Fungal infections are relatively frequent and can involve any of the paranasal sinuses. They can be broadly classified as “invasive” and “noninvasive” (Table 3.1).
a. Noninvasive. Immunocompetent patients usually develop noninvasive fungal disease, either allergic fungal sinusitis or mycetoma (“fungus ball”). Clinically, they have similar presentations with symptoms of chronic sinusitis including headache, nasal discharge, stuffiness, and facial pressure.
TABLE 3.1 Fungal Sinusitis
Noninvasive: Allergic fungal sinusitis
Chronic sinusitis; inflammatory polyps; allergic symptoms; pan-sinusitis
Eosinophilic mucus; sheets of degenerating eosinophils; Charcot-Leyden crystals; sometimes fragmented hyphae in mucus
Aspergillus; dematiaceous fungi: Bipolaris, Alternaria, Curvularia, Cladosporium
Noninvasive: Mycetoma (“fungus ball”)
Chronic sinusitis, mass lesion on imaging— usually one sinus cavity; usually nonallergic-type presentation
Large intraluminal collections of fungal hyphae; minimal mucus; minimal inflammation
Aspergillus; dematiaceous fungi: Bipolaris, Alternaria, Curvularia, Cladosporium
Invasive: Acute invasive fungal sinusitis
Severe acute sinusitis; fever; nasal discharge; ocular or neurologic deficits
Necrosis; thrombosis; hemorrhage; angioinvasive fungal hyphae in viable tissue; minimal inflammation
Common: Mucorales order—Mucor, Rhizopus, Absidia, Cunninghamella;
Uncommon: Aspergillus, Curvularia, Alternaria
Invasive: Chronic invasive fungal sinusitis
Slow, progressive onset; neurologic or orbital deficits; mass on imaging
Necrosis; angioinvasive fungal hyphae; granulomas
Allergic fungal sinusitis patients have asthma (present in >90% of cases), eosinophilia, atopy, and elevated total fungus-specific immunoglobulin E (IgE) concentrations. Endoscopy reveals thick, sticky, greenish or black to brown mucus, often described as the consistency of peanut butter. Microscopically, abundant brightly eosinophilic hypocellular mucin is present, distinct from slightly basophilic normal mucin. The mucin contains sheets of eosinophils that are degenerating and degranulating. These granules may coalesce to form the classic Charcot-Leyden crystals (e-Fig. 3.4). The most common causative organisms are dematiaceous fungi such as Bipolaris and Curvularia, Alternaria, and Aspergillus. Fungal hyphae are fragmented and widely scattered in the mucin, so they are rarely visible by H&E. Special stains such as Grocott’s Methenamine Silver (GMS) are usually necessary for identification. If the typical histologic picture is present without identifying organisms, the term allergic mucin is used. If hyphae are identified, the term allergic fungal sinusitis is used.
Patients with mycetoma have chronic sinusitis but usually lack allergic symptoms. On endoscopy, the single affected sinus has mucopurulent, cheesy, or clay-like material that microscopically consists of sheets of fungal hyphae with minimal mucin and inflammatory cells (e-Fig. 3.5).
b. Invasive. Patients with invasive fungal disease are usually immunocompromised, frequently from diabetes mellitus, bone marrow or solid organ transplantation, and occasionally human immunodeficiency virus (HIV) infection, and are at great risk of morbidity and mortality.
Patients are often severely ill with fever, cough, nasal discharge, headache, and mental status changes. They sometimes have ophthalmologic symptoms or neurologic deficits due to orbital or cranial involvement. On endoscopy, there are dark ulcers on the mucosa and associated black, greasy necrotic tissue. The fungi are angioinvasive, so they cause extensive hemorrhage and necrosis. In the viable tissue, the microscopic findings include minimal inflammation and blood vessels filled with refractile fungal hyphae (e-Fig. 3.6). The order Mucorales is most common (e.g., Mucor, Rhizopus, Absidia), but other fungi including Aspergillus species may be causative. The morphology of Mucor species includes bizarre, angulated hyphal fragments and elongated hyphae that are wide, irregular, and thick walled. Typically there is 90-degree angle branching without septation. Diabetics may also develop a chronic pattern of invasive fungal disease, often presenting as a slowly progressive orbital mass; microscopically, angioinvasive hyphae or granulomas are often present in these patients.
B. Nonneoplastic lesions. Several lesions, developmental or mechanical, can occur in the sinonasal region and can be mass-like and simulate true neoplasms.
1. Mucous impaction is an uncommon lesion that occurs mostly in children and young adults with a long history of chronic sinusitis. It represents impaction of a large amount of mucus within the maxillary antrum. Grossly, it consists of translucent gray to pink material. Microscopically, it simply consists of slightly basophilic to eosinophilic extracellular mucin with a mixture of plasma cells, lymphocytes, and neutrophils with desquamated respiratorytype epithelium.
2. Paranasal sinus mucoceles are chronic, nonneoplastic cysts that form from the obstruction of the sinus outlet by any of a number of processes. They occur most commonly in the ethmoid and frontal sinuses. Grossly, they consist of a cyst filled with mucoid or gelatinous material. Microscopically, they consist of extracellular mucin with a flattened respiratory-type epithelial lining that may have secondary squamous metaplasia.
3. Respiratory epithelial adenomatoid hamartoma (REAH) is a rare, benign, polypoid lesion characterized by an adenomatoid proliferation of respiratory-type epithelium that occurs primarily on the posterior nasal septum. Microscopically, it consists of a polypoid proliferation of variably sized, round to oval glands lined by respiratory-type epithelium with a markedly thickened basement membrane and no cytologic atypia or significant mitotic activity (e-Fig. 3.7). The gland-like structures are often in direct continuity with the surface epithelium (e-Fig. 3.8). The stroma is edematous and can resemble that of an inflammatory polyp.
C. Neoplastic lesions. A wide array of neoplasms occur in the sinonasal region (Table 3.2).
a. Schneiderian papillomas. The ectodermally derived Schneiderian membrane gives rise to three different types of benign papillomas: exophytic, inverted, and oncocytic (Table 3.3). The distinction of these papillomas is important because of their differences in behavior and risk of carcinoma development. For this reason, it is critical to entirely submit all papilloma tissues for microscopic examination.
i. Exophytic papilloma (fungiform papilloma). Most of these occur on the nasal septum, particularly anteriorly, in adults 20 to 50 years old. They are more common in men. Human papillomavirus (HPV; specifically the low risk types HPV 6 and 11) has been detected in a significant number of cases, so the virus may be important for pathogenesis. Exophytic papillomas are usually solitary and discrete, and patients present with epistaxis, unilateral nasal obstruction, or an asymptomatic mass.
TABLE 3.2 WHO Histological Classification of Tumors of the Nasal Cavity and Paranasal Sinuses
Malignant epithelial tumors
Squamous cell carcinoma
Papillary squamous cell carcinoma
Basaloid squamous cell carcinoma
Spindle cell carcinoma
Acantholytic squamous cell carcinoma
Sinonasal undifferentiated carcinoma
Salivary gland-type carcinomas
Adenoid cystic carcinoma
Acinic cell carcinoma
Clear cell carcinoma not otherwise specified
Carcinoma ex pleomorphic adenoma
Polymorphous low-grade adenocarcinoma
Small cell carcinoma, neuroendocrine type
Benign epithelial tumors
(Schneiderian papilloma, inverted type)
(Schneiderian papilloma, oncocytic type)
(Schneiderian papilloma, exophytic type)
Salivary gland-type adenomas
Soft tissue tumors
Malignant fibrous histiocytoma
Malignant peripheral nerve sheath tumor
Borderline and low malignant potential
Inflammatory myofibroblastic tumor
Extrapleural solitary fibrous tumor
Tumors of bone and cartilage
Giant cell lesion
Giant cell tumor
Nasal chondromesenchymal hamartoma
Extranodal natural killer (NK)/T-cell lymphoma
Diffuse large B-cell lymphoma
Extramedullary myeloid sarcoma
Langerhans cell histiocytosis
Primitive neuroectodermal tumor
Melanotic neuroectodermal tumor of infancy
Mucosal malignant melanoma
Germ cell tumors
Teratoma with malignant transformation
Sinonasal yolk sac tumor (endodermal sinus tumor)
From: Barnes L, Eveson J, Reichart P, Sidransky D, eds. World Health Organization Classification of Tumours. Pathology and Genetics. Head and Neck Tumours. Lyon: IARC Press; 2005. Used with permission.
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Nasal Cavity, Paranasal Sinuses, and Nasopharynx
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Heather N. Wright
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