Nasal cavity, paranasal sinuses, nasopharynx
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Last revised 17 May 2007
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Primary references, normal anatomy, normal histology
Inflammatory/infectious lesions: allergic fungal sinusitis, allergic rhinitis, Aspergillus, chronic rhinitis, cholesterol granuloma, Churg-Strauss syndrome, eosinophilic angiocentric fibrosis, fungal ball, fungal disease, granulomatous lesions, idiopathic midline destructive disease, infectious rhinitis, Kartagener syndrome, leprosy, mucocele, Mucor, myospherulosis, nasal polyps, necrotizing sialometaplasia, pertussis, pharyngitis, rhinoscleroma, rhinosporidiosis, sinusitis, sarcoidosis, steroid injections, tuberculosis, Wegener’s granulomatosis
Nasopharyngeal carcinoma: general, keratinizing squamous cell, nonkeratinizing-differentiated, undifferentiated, papillary adenocarcinoma
Sinonasal carcinoma: general, adenocarcinoma-general, low grade adenocarcinoma, intestinal adenocarcinoma, cylindrical (transitional), small cell, squamous cell, undifferentiated (anaplastic)
Hematologic conditions: lymphoma-general, angiotropic lymphoma, diffuse large B cell lymphoma, follicular lymphoma, lymphoid hyperplasia, lymphomatoid granulomatosis, mantle cell lymphoma, NK/T cell lymphoma, peripheral T cell lymphoma, plasmacytoma
Other tumors: ameloblastoma, aneurysmal bone cyst, angiomyolipoma, angiosarcoma, astrocytoma, carcinoid, chondrosarcoma, chordoma, cocaine related, craniopharyngioma, dermoid cyst, desmoplastic small round cell tumor, fibroinflammatory proliferation, fibroma, fibromatosis, fibroosseous lesions, fibrosarcoma, follicular dendritic cell, gangliocytic paraganglioma, giant cell reparative granuloma, giant cell tumor, glial heterotopia, glomus, hemangiopericytoma-sinonasal type, leiomyoma, lobular capillary hemangioma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, Masson’s tumor, melanoma, meningioma, myxoma, nasal chondromesenchymal hamartoma, nasopharyngeal angiofibroma, neurofibroma, nodular fasciitis, nonsecretory cyst, olfactory neuroblastoma, osteochondromyxoma, osteoma, papilloma, paraganglioma, pituitary adenoma, pleomorphic adenoma, psammomatoid ossifying fibroma, respiratory epithelial adenomatoid hamartoma, rhabdomyoma, rhabdomyosarcoma, Rosai-Dorfman disease, salivary gland anlage tumor, salivary gland tumors-general, schwannoma, solitary fibrous tumor, teratoid carcinosarcoma, teratoma
Miscellaneous: TNM staging, post-chemotherapy atypia, grossing, features to report
AJCC Cancer Staging Manual (6th Ed)
American Journal of Surgical Pathology (AJSP), Jan 1998 to Aug 2004
Archives of Pathology and Laboratory Medicine (Archives), Jan 1998 to Aug 2004
Human Pathology (Hum Path), Jan 1998 to July 2004
Modern Pathology (Mod Path), Jan 1998 to July 2004
Rosai, J: Ackerman’s Surgical Pathology (9th Ed); Mosby-Year Book, Inc., 2004
Sternberg, S: Diagnostic Surgical Pathology (4th Ed); Lippincott Williams & Wilkins, 2004
Journal search terms: nose, nasal, paranasal, sinus, nasopharynx
Please refer to these primary references for more detailed discussions and photographs
Nasal cavity, paranasal sinuses and nasopharynx form functional unit
Nasal cavity
Divided into olfactory region (superior nasal turbinates and opposed septum) and respiratory region (rest of cavity)
Nasal chambers are on either side of median plane formed by nasal septum
Bounded above by cribriform plate; bounded laterally by turbinates
Bulla ethmoidalis: elevation on lateral wall of middle meatus, site of opening of middle ethmoid meatus
Choanae: posterior opening of nasal cavity, communicates with nasopharynx
Columella: anterior extreme nasal septum
Nares: anterior openings of nasal cavity
Vestibule: slight dilation inside anterior aperture of nostril, bounded laterally by ala and lateral crus of greater alar cartilage and medially by medial crus of greater alar cartilage; lined by skin containing hair and sebaceous glands
Lateral wall: contains superior, middle and inferior nasal turbinates (conchae); below each is corresponding nasal passage or meatus
Sphenoethmoidal recess: above superior turbinate, site of opening of sphenoidal sinus
Turbinates (concha): comprise lateral walls of each nasal cavity
Superior meatus: along upper border of middle turbinate, site of opening of posterior ethmoid meatus
Middle meatus: below and lateral to middle turbinate
Nasopharynx
Respiratory passage above and behind the soft palate
Part of pharynx, which also includes oropharynx and hypopharynx
Begins anteriorly at posterior turbinates and extends along plane of airway to the level of the free border of the soft palate
Anterior wall is perforated by posterior nares (choanae)
Posterior wall is also its roof, as well as the posterior base of skull; extends inferiorly to level of free border of soft palate where oropharynx begins
Lateral wall contains ostium of eustachian tube, surrounded by mucosa covered cartilaginous prominence; ostium is anterior to pharyngeal recess (fossa of Rosenmuller)
Paranasal sinuses
Diverticula of nasal cavity that extend into neighboring bones
Ethmoid sinuses: between the orbits; well developed at birth
Frontal sinuses: most anterior, above the orbits; small/rudimentary at birth; develop through puberty
Maxillary sinuses: under the cheeks; small/rudimentary at birth; develop rapidly during childhood until permanent teeth develop
Sphenoid sinuses: most posterior at base of brain; small/rudimentary at birth; develop rapidly during childhood until permanent teeth develop
Ohngren’s line: connects medial canthus of eye to angle of mandible; used to divide maxillary sinus into anteroinferior portion (infrastructure), associated with good prognosis for carcinomas, and superoposterior portion (suprastructure), with a poor prognosis for carcinomas
Nasal cavity
Lined by stratified squamous and respiratory type pseudostratified columnar epithelium, separated by transitional epithelium in some places
Respiratory mucosa (also called Schneiderian membrane) may contain goblet cells; may undergo squamous metaplasia
Superior third of nasal septum, superior turbinate and cribriform plate are covered with thinner olfactory mucosa, usually patchy in adults, which has neuroendocrine features
Seromucinous glands (resembling salivary glands) are present in submucosa, numerous near eustachian tube opening of nasopharynx, may undergo oncocytic metaplasia with increasing age
Normally no lymphoid tissue
Nasopharynx
Lined by stratified squamous epithelium (inferior anterior and posterior walls and anterior lateral walls) and respiratory type epithelium (around nasal choanae and roof of posterior wall); remaining areas have mixtures of squamous and respiratory or intermediate epithelium (also called transitional although it does not resemble urothelium ultrastructurally)
Intermediate epithelium is usually concentrated as a wavy ring at junction of nasopharynx and oropharynx
Seromucinous glands may undergo oncocytic metaplasia, and rarely form a mass or obstruct eustachian tube
Abundant lymphoid tissue present, particularly at rim of eustachian tube opening (Gerlach’s tonsil); functionally equivalent to that of GI tract or mucosal-associated lymphoid tissue (MALT)
Paranasal sinuses
Mucosa is continuous with nasal cavity and identical (respiratory type epithelium), but thinner and with fewer goblet cells and seromucinous glands
Normally no lymphoid tissue
Inflammatory/infectious lesions
Due to Aspergillus, Curvularia lunata or Fontana-Masson positive dematiaceous fungi (Drechslera, Bipolaris, Exoserohilium)
Produces “allergic mucin” (lamellated collection of inspissated inflammatory debris with numerous eosinophils and Charcot-Leyden crystals) and fungal hyphae
Mucin may require curettage to remove, may recur
May cause bony erosion due to pressure remodeling, but usually not invasive
Affects immunocompetent patients ages 20-49 years with chronic allergy, asthma, nasal polyps or sinusitis
May be due to tenacious mucin that traps normally nonpathogenic, low-virulence fungal organisms
Diagnosis initially missed in half of cases
Treatment: surgical removal, low-dose corticosteroids, possibly immunotherapy for underlying allergy
Gross: green, brown or black mucin with consistency of clay; gray-brown, laminated, gelatinous or translucent cut surface
Micro: mucosal edema, marked eosinophilic infiltrate, allergic mucin in 92%, eosinophils may have degenerative changes of smudged, elongated or basophilic nuclei; also plasma cells and lymphocytes; rare noninvasive fungal hyphae (often found only with GMS stain), rare neutrophils
References: Hum Path 2004;35:474
Also called hay fever
Due to exposure to plant pollens, fungi, dust mites, animal allergens
Affects 20% of US population
IgE mediated
Micro: mucous secretions have neutrophils and prominent eosinophils
Causes fungus balls (see below) in nasal antrum of immunocompetent patients with minimal inflammatory response, microabscesses or multinucleated giant cells
Also causes invasive aspergillosis, regardless of immune status, with extension into retroorbital region, cranium or parapharyngeal space; often fatal
Also causes allergic fungal sinusitis (see above)
Micro: septate hyphae that branch at 45 degrees
DD of invasive fungal infections: Zygomycetes, Pseudallescheria boydii, Paecilomyces, Alternaria, Cladosporium trichoides, Fusarium
Sequel to acute rhinitis (symptoms lasting 6 weeks or less), with development of secondary bacterial infection
Associated with deviated septum or nasal polyps; also ulceration and infection extending into sinuses
Rare in nasal cavity or sinuses; usually associated with chronic middle ear disease
May be a reaction to hemorrhage
Treatment: excision
Case reports: maxillary sinus lesion of 38 year old man (Archives 2002;126:217)
Micro: foreign body giant cells surrounding empty, needle shaped spaces (cholesterol clefts representing cholesterol crystals that have dissolved due to alcohol in staining process), chronic inflammatory infiltrate, hemosiderin laden macrophages, dilated lymphatics
2/3 have nasal polyps or mucosal crusting
Micro: discrete necrotizing granulomas with numerous eosinophils, often forming microabscesses
DD: Wegener’s granulomatosis
Eosinophilic angiocentric fibrosis
Very rare; unknown cause
May be mucosal counterpart of granuloma faciale
Involves any portion of upper respiratory tract, often nasal septum and sinus mucosa
Usually women, mean age 44 years
Case reports: 45 year old man with no history of allergic disease (Archives 2004;128:90)
Treatment: corticosteroids, resection
Micro: thick collagen bundles, perivascular onion-skin fibrosis with eosinophil-rich inflammatory infiltrate; no granulomas, no necrosis, no vasculitis
DD: granuloma faciale (inflammatory vascular reaction with facial papules, neutrophilic and eosinophilic infiltrate, vasculitis with fibrinoid material in vessel walls)
Also called mycetoma, chronic noninvasive fungal sinusitis
Usually immunocompetent patients, often prior history of sinus disease, trauma or foreign body
Gross: grumous, friable, gray-brown-black material, often with clotted blood
Micro: tightly packed extramucosal hyphae, usually in maxillary antrum; no/minimal host response, no allergic mucin or tissue invasion; usually due to Aspergillus (hyphae with septation and branching at 45 degree angles, no spores)
Includes sinusitis (acute fulminant, chronic invasive), mycetoma, saprophytic infestation (fungal spores on mucous crusts of respiratory passages) and allergic fungal sinusitis
May develop post-steroid injection with amorphous foreign material
Cholesterol granulomas in paranasal sinuses are rare
Also due to fungal infections, myospherulosis, tuberculosis, Wegener’s granulomatosis
Idiopathic midline destructive disease
Diagnosis of exclusion
Gross: usually perforated nasal septum, perforated palate, erosion of antral bone or ulceration of skin overlying nose or antrum
Micro: acute and chronic inflammatory cells with variable necrosis; may have multinucleated giant cells or granulomas; no atypical lymphocytes, no fibrinoid necrosis of vessels, no prominent eosinophils
DD: Wegener’s granulomatosis (different clinical findings)
Also called “common cold”
Due to adenovirus, echovirus and rhinoviruses
Symptoms: catarrhal discharge, thick, edematous, erythematous nasal mucosa; enlarged turbinates
May cause pharyngotonsillitis; may have secondary bacterial infection
Situs inversus, bronchiectasis and sinusitis, due to defective ciliary action
Affects nasal mucosa in 95% of patients; may be initial manifestation of disease
Usually affects nasal septum and inferior turbinate
Micro: early - plasma cells with lesser numbers of histiocytes and lymphocytes; later - broad sheets of histiocytes with foam cells; well formed granulomas of tuberculous type are uncommon
Positive stains: acid fast stains
Also called pseudocyst
Complication of chronic sinusitis due to outflow obstruction
May destroy contiguous bones and resemble a neoplasm
2/3 in frontal sinus; also anterior ethmoid sinus
Micro: inflammatory cells and mucin lift epithelium of sinus and periosteum away from underlying bone; epithelium may undergo squamous metaplasia; extravasation of mucin into lamina propria with muciphages
Relatively common life-threatening fungal infection, associated with diabetic ketoacidosis, poor glycemic control or immunosuppression
Spreads rapidly across nerves and tissue planes to blood vessels of orbit and brain, causes thrombosis, hemorrhage and infarction
Member of phylum Zygomycota, class Zygomycetes, order Mucorales; found in high-organic matter and soil
Mortality rate of 48%
Case reports: 29 year old man post bone marrow transplant with psychosis and gingival lesion (Archives 2000;124:883)
Micro: broad nonseptate hyphae branching at 90 degrees, accompanied by numerous neutrophils and histiocytes within granulation tissue
Iatrogenic lipogranuloma after hemostatic packing of nasal cavity or paranasal sinuses with petrolatum based ointment and gauze
Resembles subcutaneous disease of East Africa
Micro: large tissue spaces with saclike structures containing brown spherules resembling Prototheca but actually clumped red blood
cells
Negative stains: GMS
Common; not neoplastic, but may fill entire nasal cavity or extend into cranial cavity or orbit
In children, must rule out cystic fibrosis
Often recur due to persistence of causative factors
Micro: edematous lamina propria with variable inflammatory infiltrate including eosinophils; subtypes include angiectatic (angiomatous), cystic, edematous, fibrous, glandular
Angiectatic polyps
Extensive vascular proliferation and ectasia with pseudoamyloid deposition that simulates malignancy
Due to marked reactive and reparative changes
May cause life threatening epistaxis, facial deformity or bone erosion and remodeling
Gross: gelatinous, semitranslucent masses with smooth, blue-gray glistening surface
Micro: dilated thin walled vessels in pools of eosinophilic material, associated with patchy necrosis and atypical spindle cells; associated with choanal polyps arising in paranasal sinuses and protruding into nasopharynx
DD: angiofibroma, hemangioma
References: Archives 2000;124:406
Antrochoanal polyp
4-6% of nasal polyps
Frequently occur in childhood
90% solitary
Arise from wall of maxillary antrum, extending through large primary or secondary maxillary ostium into nasal cavity
May pass into choanae or nasopharynx
Gross: long narrow stalk with firm, fibrous body
Micro: thin surface mucosa with no thickened basement membrane; stroma with stellate cells, less edema and fewer glands than inflammatory polyp; may have prominent dilated vessels with thrombosis or infarct; prominent eosinophils in only 20%
Atypical stromal cells
Common; have prominent cytoplasm, enlarged hyperchromatic nuclei resembling “radiation fibroblasts” or sarcoma
More common in younger patients or those with prominent fibrous stroma
No increased cellularity, no prominent vasculature, no mitotic figures
Resemble polyp on low power
Cystic fibrosis polyp
Must rule out cystic fibrosis in any child with nasal polyps
Present in 20% with cystic fibrosis
May arise up to 12 years before clinical diagnosis; rarely is initial manifestation of disease in adults
Micro: similar to inflammatory polyps, but no basement membrane thickening, no submucosal hyalinization, no/rare stromal eosinophils; may have large cystic glands with inspissated mucin in lumina; mucous glands, cysts and mucous contain predominantly acid mucin
Positive stains: purple-blue mucin with combined Alcian blue PAS stain (vs. red for inflammatory polyp)
Inflammatory polyp
Most common type of nasal polyp
Due to recurrent attacks of rhinitis (allergic, inflammatory)
Most people with polyps are NOT atopic; only 0.5% with atopy develop polyps
Usually ages 30 years or older (rarely < age 20 years)
Often recurs after surgery
Often associated with asthma, chronic rhinitis, aspirin intolerance (14%)
Gross: usually multiple and bilateral and involve nasal cavity and paranasal sinuses; have translucent, moist or edematous cut surface (opaque areas may represent papilloma); broad base of attachment is present; usually not destructive
Micro: respiratory epithelium, often with squamous metaplasia, edematous and loose stroma with hyperplastic mucous glands, inflammatory infiltrate (lymphocytes, plasma cells, eosinophils, neutrophils, mast cells); mucosa may be ulcerated or infected; basal membrane may be thickened; may have “bizarre” stromal cells (large and pleomorphic) due to reactive changes; may have prominent glandular component
DD: papilloma
Benign process that resembles squamous cell carcinoma or mucoepidermoid carcinoma
Occurs after surgery on nose or sinuses
Micro: necrosis of seromucinous glands with secondary squamous metaplasia and reactive atypia
Possibly life-threatening nasopharyngeal infection caused by Bordetella pertussis
Causes progressive, repetitive paroxysmal coughing, mild systemic complaints and lymphocytosis
Worldwide causes 60 million severe cases and 1 million deaths annually
In US, 5000-7000 annual cases, deaths usually only in infants younger than 1 year
Outbreak in Wisconsin (USA) in 1993 with attack rates of 23% (ages 30-49 years) and 33% (ages 50+)
Vaccination widely given, but efficacy may wane 4 years after last dose
Diagnosis: culture requires 5-7 days, also PCR
Treatment: erythromycin (but some cases are resistant)
References: Archives 2002;126:173
Often secondary bacterial infection by Streptococcus pneumonia or Staphylococcus aureus
Severe infections occur in infants or adults with neutropenia, HIV, diabetes, antibiotics
Streptococcus pneumonia pharyngitis: treat with antibiotics to prevent subsequent glomerulonephritis or rheumatic fever
Viruses: rhinovirus, echovirus, adenovirus, respiratory syncytial virus, influenza
Also called scleroma
Rare; chronic granulomatous disease affecting nasal cavity (95-100%), nasopharynx (18-43%), larynx (15-40%), trachea (12%) or bronchi (2-7%) caused by Klebsiella rhinoscleromatis
Usually low socioeconomic environments of central/South America, Africa, Middle East, Philippines, India; rare in US (usually immigrants)
Most common in young adults
Initially nonspecific rhinitis, then purulent, fetid rhinorrhea with crusting; then granulomatous stage with blue-red granular nasal mucosa with intranasal rubbery nodules or polyps, epistaxis, anosmia, enlargement of uvula, anesthesia of soft palate, variable airway obstruction; finally sclerosis
Treatment: tetracycline or trim-sulfa, possibly steroids, surgery to correct scars or stenosis
Microbiology: MacConkey agar cultures are 50-60% sensitive; bacteria is gram negative, encapsulated, nonmotile diplobacillus, member of Enterobacteriaceae, not normal flora, infective via drops or contamination of material that is inhaled
Case reports: polypoid intranasal mass in 32 year old woman (Archives 2001;125:159)
Micro: initially inflamed granulation tissue; later hyperplastic mucosa with pseudoepitheliomatous squamous hyperplasia, granulomatous inflammation, foamy macrophages (Mikulicz cells containing bacteria) and plasma cells with Russell bodies; variable vasculitis and ulceration; late-fibrosis, lymphocytes and plasma cells but no Mikulicz cells
Positive stains: PAS, Giemsa, Steiner or Hotchkiss-McManus stains for gram negative bacteria
EM: large phagosomes containing bacilli and finely granular material (antibodies on bacterial surface and aggregates of bacterial mucopolysaccharides)
DD: Rosai-Dorfman disease, leprosy
Fungus endemic in India
Gross: hyperplastic polypoid masses of nasal cavity
Micro: huge, thick walled sporangia up to 200 nm with >1000 spores; surrounded by intense inflammatory infiltrate of neutrophils, lymphocytes and plasma cells
Acute sinusitis
Often preceded by acute or chronic rhinitis
Usually self limited or well controlled with supportive treatment
Acute invasive fungal sinusitis (fulminant invasive fungal sinusitis)
Often seen in immunocompromised or diabetic patients, often ocular involvement or intracranial extension, associated with progressive disease and death
Treatment: vigorous systemic antifungal therapy
Micro: vascular invasion by fungi is present and may cause thrombi; also neutrophils, eosinophils, tissue necrosis and hemorrhage
Chronic sinusitis
Mixed bacterial flora, develops after acute sinusitis
May produce osteomyelitis of orbit or thrombophlebitis of dural venous sinus
Most commonly in maxillary sinus, and preceded by periapical infection from floor of sinus
May need biopsy for accurate diagnosis
Noninvasive fungal disease is often Aspergillus
Treatment: surgery to control disease may be necessary
Gross: edematous mucosa which blocks drainage and may cause empyema of sinus
Micro: glandular hyperplasia, squamous metaplasia, basement membrane thickening, inflammatory cells including eosinophils, edema; bone may show thickening and remodeling with osteoblastic rimming and fibrosis of bone marrow spaces; presence of allergic mucin (lamellated collection of inspissated inflammatory debris) suggests fungal organisms
Chronic noninvasive fungal sinusitis
Also called indolent fungal sinusitis
Associated with diabetes, immunocompromise or endemic areas (Sudan, Saudi Arabia)
Micro: fungi with surrounding foreign body inflammatory response or granulomas and tissue invasion; no vascular invasion by definition
5% of patients have upper airway involvement, usually in nasal septum or inferior turbinate
Micro: granulomas without caseous necrosis
DD: tuberculosis
Micro: granulomas with amorphous area (residual injected substance) surrounded by palisading histiocytes
Rare; usually associated with cervical lymphadenopathy
Usually isolated infection and not secondary spread from pulmonary infection
Diagnosis: culture or PCR
Gross: ulcerated or polypoid lesion of nasal septum or inferior turbinate; variable septal perforation
Micro: poorly formed granulomas, usually no necrosis; organisms rare
Rapidly progressive condition involving nasal cavity, lungs and kidney
Biopsies of 5 mm or more improve diagnostic yield
Note: lymphocyte rich biopsies are unlikely to be Wegener’s and more likely represent lymphoma
Diagnostic for Wegener’s: granulomatous inflammation, necrosis and vasculitis, in addition to clinical involvement of lung or kidney; OR two of three microscopic features and lung and kidney involvement
Probable: two of three microscopic features and (lung or kidney involvement) but not both
Suggestive: one of three microscopic features and lung and kidney involvement
Suspicious: one of three microscopic features and (lung or kidney involvement) but not both
Nonspecific: no microscopic features, either lung or kidney involvement
Gross: early disease usually lacks destruction of cartilage or bone
Micro: leukocytoclastic vasculitis of arterioles, small arteries and veins with geographic necrosis surrounded by palisading histiocytes, variable poorly formed granulomas with minimal lymphocytes; variable giant cells; granulomas and giant cells are distant from vessels or adjacent/within vessel wall; also epithelial ulcers; vessel may be obliterated by inflammatory cells and thrombus and be difficult to identify without elastic stain; all stages of vasculitis are present (acute: neutrophils with fibrinoid necrosis; chronic/healed: narrowed or obliterated lumina with concentric rims of perivascular collagen); usually no significant lymphoid infiltrate
Positive stains: elastic stains to identify badly damaged vessels
Negative stains: EBV
DD: Churg-Strauss syndrome, NK/T cell lymphoma, idiopathic midline destructive disease, tuberculosis, lymphoma, eosinophilic angiocentric fibrosis, cocaine-related lesions, systemic lupus erythematosus, necrotizing vasculitis from other causes
Nasopharyngeal carcinoma
Nasopharyngeal carcinoma-general
Demographics vary by region
Africa: common; #1 childhood cancer; associated with EBV
South China: most common cancer in adults (18% of cancers in Hong Kong), rare in children
US: rare in adults or children
70% male
Strongly associated with EBV infection for undifferentiated and nonkeratinizing subtypes
Laboratory: IgG against early EBV antigen is suggestive, but has 30% false positives; IgA against viral capsid antigen has 9-18% false positives
Diagnosis: blind biopsies, particularly in fossa of Rosenmuller, are recommended if diagnosis is suspected (70% sensitive)
Tumors arising from fossa of Rosenmuller frequently extend to paranasopharyngeal space, then along trigeminal nerve
Often metastasizes to regional nodes; common presentation is unilateral cervical lymphadenopathy; 25% have bilateral nodal metastases
May have distant metastases to bones
After radiation, risk of 0.4% of subsequent carcinoma in nasal cavity of nasopharynx; differentiate from recurrence based on > 5 year delay, different histology, EBV negative (Hum Path 2000;31:227)
Treatment: radiation therapy; post-radiation 10 year survival is 43%
Good prognostic factors: younger age, lower stage, ipsilateral metastases, metastases limited to upper neck, no involvement of cranial nerves, orbit or intracranial; not keratinizing squamous cell subtype
Gross: may not be identifiable
Micro: either keratinizing, nonkeratinizing-differentiated or nonkeratinizing-undifferentiated (see below)
Nodal metastases: resemble diffuse large cell lymphoma but are focal, have large vesicular nuclei with single prominent nucleoli; may have marked eosinophilia resembling Hodgkin’s lymphoma; may have marked cystic changes resembling bronchial cleft cysts, may have granulomatous reaction with necrosis
Positive stains: keratin, EMA, EBV, EBER; often p53, variable CEA, variable S100
EM: tonofilaments and complex desmosomes
Keratinizing squamous cell carcinoma
Also called WHO type 1
Minority of tumors
Often EBV-, older age group
5 year survival is close to 0%
Treatment: don’t respond to radiotherapy, but tend to remain localized
Micro: squamous differentiation with intercellular bridges or keratinization in most of tumor; rarely adenoid or acantholytic forms that mimic adenocarcinoma
Nonkeratinizing carcinoma-differentiated
Also called WHO type 2
Rare in childhood
5 year survival 35-50%
Treatment: variably radiosensitive, may metastasize to regional lymph nodes
Micro: cells lack squamous differentiation but have variable levels of maturation; cells are stratified with well defined cell margins that interdigitate in a payment stone pattern; no mucin or glandular differentiation; variable chronic inflammatory cells
Positive stains: CK5/CK6, CK8, CK13, CK14, CK19
Negative stains: CK4, CK7
Nonkeratinizing carcinoma-undifferentiated
Also called WHO type 3
Very rare in US, common in Taiwan and China (EBV endemic area)
Often called lymphoepithelioma, although lymphocytes are not neoplastic and some cases lack lymphocytes
Bimodal age distribution (teens, 50+); in Taiwan, median age is 58 years (range 36-75 years); 2/3 male
5 year survival after radiation therapy alone is based on stage--confined to nasopharynx (stage I): 50-60%; cervical node involvement (stage II): 20-30%; invasion of surrounding structures (stage III): 5-30%
Survival does not vary based on histologic patterns below
Tends to metastasize to regional lymph nodes
Treatment: supervoltage radiotherapy and cis-platinum based chemotherapy (70-90% 5 year survival overall)
Case reports: 2 cases of undifferentiated carcinoma with focal glandular differentiation (Archives 2000;124:1369)
Micro: syncytial arrangement of uniform cells with indistinct cell margins; cells have vesicular nuclei and prominent nucleoli; may have spindle cells and scattered effete (“worn out”) cells with shrunken, hyperchromatic nuclei that are more variable than sinonasal undifferentiated carcinoma; usually (but not always) non-neoplastic lymphocytic infiltrate (often T cells) with plasma cells, eosinophils and macrophages; patterns below may be mixed; no necrosis
Regaud pattern: neoplastic cells form well defined cohesive nests and cords separated by inflammation
Schminke pattern: inflammatory cells permeate cells nests causing isolation of carcinoma cells within lymphoid background, resembling lymphoma; tumor cells have thin chromatin rims and lack lacunae
Positive stains: keratin (particularly helpful for Schminke pattern, CK 5/6, CK8, CK13, CK19), EBER1 by in situ hybridization
Negative stains: CK4, CK7, CK14
DD: sinonasal undifferentiated carcinoma, nonkeratinizing squamous cell carcinoma (cells are arrangement in pavement stone pattern with more abundant eosinophilic cytoplasm and distinct cell borders), Hodgkin’s lymphoma (Reed Sternberg cells are binucleated with no thin chromatin rims or have lacunar pattern), melanoma
References: AJSP 2002;26:371 (vs. sinonasal undifferentiated carcinoma)
Papillary adenocarcinoma of nasopharynx
Rare if exclude those of minor salivary gland origin
Arise from mucosa
60% males; median age 33 years (range 11-64 years); not associated with wood dust exposure or other known factors
Typically confined to nasopharynx
Excellent prognosis; slow growing and indolent; rarely recurs; no metastases reported to date
Treatment: surgery (transpalatal approach)
Gross: exophytic or pedunculated mass; 0.3 to 4.0 cm
Micro: papillary with arborization and fibrovascular cores or glandular with cribriform or back to back glands; lined by cuboidal or columnar cells with pink cytoplasm and round/oval nuclei that are variably clear or hyperchromatic; mild to moderate nuclear pleomorphism, no/rare nucleoli or mitotic figures; occasionally psammoma bodies; “clean” background without hemorrhage or necrosis; no angiolymphatic invasion or perineural invasion; no goblet cells
Positive stains: keratin (diffuse), EMA (diffuse), CEA (focal), PAS (intracytoplasmic granules), mucin (intracellular or luminal)
Negative stains: GFAP, S100, thyroglobulin
DD: papillary thyroid carcinoma (thyroglobulin+, no epithelial dysplasia), intestinal adenocarcinoma-papillary type (nasal cavity and paranasal sinuses, usually wood dust exposure, more papillary and less glandular, tall columnar and goblet cells, “dirty” background with hemorrhage and inflammation), low grade papillary adenocarcinoma of salivary gland origin (rare in nasopharynx, arises from minor salivary glands in submucosa, not surface epithelial, usually S100+, aggressive with local recurrence (27%) and nodal metastases (17%))
Sinonasal carcinoma-general
Unusual, <1% of cancer deaths in US
Risk factors: nickel refiners, woodworkers
Usually HPV and EBV negative
Sites: within nose - usually vestibule and lateral wall; rarely septum; sinus - usually ethmoid, rare in frontal sinus
Usually diagnosed late with extensive bony destruction
Often extends locally; nodal spread is uncommon; metastases to lungs and occasionally bone
5 year survival is 60%
Treatment: surgery and radiation therapy; relapse usually within 2 years
Prognostic factors: stage, extension to pterygomaxillary fossa, invasion of dura
Micro: papillary subtypes have well developed fibrovascular cores; resemble fungiform papilloma but with widespread, severe nuclear abnormalities with pleomorphic, hyperchromatic, disorganized squamous cells; may have suprabasilar squamous cells
10% of sinonasal malignancies
Usually middle turbinate or ethmoid sinus, extending laterally to orbit or superiorly into anterior cranial fossa
Appear to arise from sinus mucosal lining, not underlying glands
Locally aggressive; nodal metastases are rare
Tubulopapillary tumors with minimal atypia are usually indolent
Histologic types are salivary gland, low grade, intestinal type
Micro: well differentiated tubulopapillary patterns, often with goblet cells and resembling colorectal carcinoma; may resemble small intestinal mucosa with resorptive, goblet, Paneth and endocrine cells; rarely coexists with atypical carcinoid
References: AJSP 2004;28:1026 (immunostaining differences between subtypes), Hum Path 2003;34:1101 (CK7/CK20 staining)
Low grade (seromucinous) adenocarcinoma
Median age 54 years, but range of 9-75 years
No site or gender predilection
No known risk factors
Good prognosis, although 30% recur; 78% are disease free after 6 years; death from disease due to local invasion, not metastases
Micro: papillary or tubular architecture of back to back glands lined by columnar cells with uniform nuclei; intracellular and extracellular mucin; often no nuclear stratification and mild to moderate pleomorphism; usually rare mitotic figures; rarely has complex papillary pattern with psammoma bodies; few goblet cells, necrosis uncommon
Positive stains: CK7 (75%, stains respiratory type epithelium and submucosal seromucous glands)
Negative stains: CK20, CDX2, MUC2
DD: oncocytic papilloma (stratified epithelium, no true glandular lumina, more abundant myxomatous stroma); intestinal type adenocarcinoma (colonic-type epithelium, more atypia), papillary thyroid carcinoma (thyroglobulin+)
Intestinal type (enteric) adenocarcinoma
Strong association with chronic exposure to fine hardwood dusts from woodworking industry (relative risk of 70-500x), who historically constituted 20% of these patients after interval of mean 40 years; also exposure to leather dust
Occupational cases involve men (85-95%), ethmoid sinus
Sporadic cases have no gender preference
Mean age 58 years for occupational and sporadic cases
5 year survival is 20-50%, although may have protracted clinical course with local recurrences and ultimate invasion of orbit and cranial cavity
3 year cumulative survival by histologic type: papillary I: 82%; papillary II: 54%; papillary III: 36%; alveolar-goblet: 48%; signet ring: 0%, transitional: 71%
Regional nodal metastases in 8%, distant metastases in 13%; tumors may change histologic type over type
May have tumor necrosis with sepsis
Xray: important in determining extent of disease and operative approach; early-soft tissue mass; late-osteodestruction and invasion of orbit or cranial cavity
Treatment: surgical excision with lateral rhinotomy; possibly radiotherapy; neck dissection not indicated since cervical nodal metastases are rare
Gross: polypoid, papillary or nodular, variable color, usually friable; may be ulcerated, hemorrhagic or mucoid
Micro: often high grade; resemble normal or neoplastic colonic or small intestinal epithelium; papillary tumors may be intramucosal or invasive; usually resemble colonic adenocarcinoma with back to back glands of pleomorphic columnar cells with intracellular mucin, but no prominent goblet cells; may have sheets of tumor cells, colloid-type tumors, signet ring cells; rarely resembles normal intestinal mucosa or villous adenoma; may contain Paneth or enterochromaffin cells
Klenisasser and Schroeder classification (Arch Otorhinolaryngol 1988;245:1):
Papillary tubular cylinder cell (frequencies -- 18%-I, 36%-II, 20%-III), alveolar goblet cell (13%), signet ring cell (3%), transitional (11%)
Also well differentiated (I), moderately differentiated (II) and poorly differentiated (III)
Papillary tubular cylinder cell-I (well differentiated): also called papillary type; fibrovascular fronds and glands/tubules covered by tall ciliated columnar (cylinder) cells; may have polarization of columnar cells with long axes perpendicular to basement membrane; may be stratified and crowded; pink cytoplasm and round/oval nuclei, variable chromatin and nucleoli; may have goblet cells; variable mitotic figures; often hemorrhagic, necrotic or inflammatory background; either invasive or in situ over broad front; may have bland cytology and resemble a villous adenoma or normal intestinal mucosa, but are still locally aggressive and destructive; may have indolent disease that causes death 10 years later
Papillary tubular cylinder cell-II (moderately differentiated): also called colonic type; well to moderately differentiated glands; resembles colonic adenocarcinoma; may have cystic spaces with intracystic papillary projections
Papillary tubular cylinder cell-III (poorly differentiated): also called solid type; diffuse proliferation of small cuboidal cells with pink to amphophilic cytoplasm, round and vesicular nuclei, often nucleoli, often mucin droplets; minimal gland formation
Alveolar-goblet cell: also called mucinous; glands distended with mucus or pools of mucin containing individual glands or strips of epithelium with admixed goblet cells
Signet ring: also called mucinous (as is alveolar-goblet cell); composed of small groups or single signet ring cells in pools of mucin; no strips of epithelium
Transitional: also called mixed; mixture of two of above types
Positive stains: CK7 or CK20, CDX2 (may be focal), MUC2 (44%), p53 (18%), chromogranin and NSE (diffuse and strong intensity)
Negative stains: CEA (may be weak/focal)
DD: metastatic adenocarcinoma (uncommon from GI tract, usually from kidney, also lung, breast, testis, but must exclude clinically; also usually weak/negative for chromogranin and NSE, strong CEA, CK7 negative; staining is opposite for sinonasal intestinal carcinoma), papillary rhinosinusitis (may be papillary, but papillae are short and blunt; has “clean” background, thick and hyalinized basement membrane, ciliated surface cells, no atypia, prominent eosinophils), papillary adenocarcinoma of nasopharynx (usually not in nasal cavity or paranasal sinuses, usually not associated with wood dust exposure, more glandular, less papillary, few columnar / goblet cells, “clean” background)
References: AJSP 2003;27:1390 (CDX2-letter)
Cylindrical (transitional) cell carcinoma
Micro: stromal infiltration and atypia are usually obvious; may have intracellular mucin; rarely yolk sac-like features
DD: papilloma (no stromal invasion), post-chemotherapy changes
Very rare; resembles pulmonary oat cell carcinoma
More common in paranasal sinuses than nasal cavity
Mean age 51 years (range 38-68 years) in small study
Usually localized aggressive disease without metastases
Micro: diffusely cellular or nests of monotonous epithelial-type tumor cells with minimal cytoplasm, hyperchromatic nuclei, frequent mitotic activity with abnormal mitotic figures, large areas of necrosis; no evidence of neural differentiation; may have components of adenocarcinoma or squamous cell carcinoma
Positive stains: AE1-AE3, CAM5.2, neuron-specific enolase, chromogranin, synaptophysin
Negative stains: TTF1 (AJSP 2000;24:1217), S100, EBV
DD: olfactory neuroblastoma, post-chemotherapy changes
References: Archives 2003;127:461 (flow cytometry); Hum Path 1998;29:826
2/3 male; usually age 50+ years; rare in patients < 40 years old
Associated with cigarette smoking, nickel ore exposure, Thorotrast; possibly job related exposure to chromium, isopropyl alcohol and radium
Most common histologic subtype
Recurrences are common; death usually due to local spread
Nasal cavity carcinoma associated with 6-28% second primary neoplasms (40% in head and neck, also lung, breast, GI)
Maxillary antrum carcinoma associated with 5% incidence of second primary carcinoma in contralateral antrum, but no increased incidence at other sites
Micro: usually high grade with variable keratinization; nonkeratinizing tumors may resemble intermediate cells of papilloma or urothelium, often grow as large cell nests and cords with mild atypia
Unusual variants are spindle cell (keratin+) and verrucous carcinoma
Positive stains: CK4 (30%), CK5/6, CK7 (60%), CK8, CK13, CK14, CK19
DD: post-chemotherapy changes
Undifferentiated (anaplastic) carcinoma
Rare; very aggressive, median survival 10-18 months
Young adults and elderly (mean age 58 years, range 20-81 years), 2/3 male
75% men, 85% smokers
May be associated with nickel exposure
Mass in nasal cavity, maxillary antrum, ethmoid sinuses, often with extension into sphenoid sinus, frontal sinus, orbit and cranial cavity
Associated with prior nasopharyngeal carcinoma treated with radiation 6-26 years earlier
Treatment: none (surgical resection difficult, chemoradiation therapy not useful)
Micro: nests, cords and sheets of small to large polygonal cells with distinct cell borders, moderate eosinophilic cytoplasm, pleomorphic nuclei with diffuse to coarsely granular chromatin, prominent nucleoli, extensive necrosis and apoptosis, frequent mitotic figures, extensive angiolymphatic invasion; no evidence of neuroendocrine differentiation (i.e. no Homer Wright rosettes, no fibrillary background, no ganglion-like cells); no squamous or glandular differentiation, no dense lymphoplasmacytic infiltrate
Positive stains: CK7 (50%), CK8 (100%) CK19 (50%], Ki-67 (most cells, variable intensity), NSE (18-50%), EMA (18%), CD99 (14%)
Negative stains: CK 5/6, CK13, EBV, PLAP, CEA, S100, EBER1 by in situ hybridization, chromogranin, synaptophysin
EM: rare dense core granules in individual cells
DD: olfactory neuroblastoma, nasopharyngeal undifferentiated carcinoma (syncytial growth of cells with uniform nuclei with vesicular chromatin in inflammatory stroma), small cell carcinoma, lymphoma, melanoma, rhabdomyosarcoma
References: AJSP 2002;26:371 (vs. nasopharyngeal carcinoma undifferentiated), AJSP 2001;25:156 (stains/EBV)
Hematologic conditions
May present as sinonasal or nasopharyngeal mass
Almost always non-Hodgkin’s lymphoma
Most patients are elderly but broad age range
Often bulky lesions affecting multiple sinuses and nasal cavity, with extension into nasopharynx
5 year survival is 55% for stage I/II
Most common: NK/T cell, diffuse large B cell, peripheral T cell; mantle cell lymphoma most common in nasopharynx
Also called intravascular lymphoma; different from angiocentric lymphoma
Most tumor cells are intravascular and don’t infiltrate vessel wall
Considered a subtype of diffuse large B cell lymphoma
Most common lymphomas of nasal cavity and paranasal sinuses in US and Western Europe; also most common type in children
More common in paranasal sinuses than nasal cavity; may invade orbit
Case reports: T cell rich variant in ethmoid sinus (Archives 2000;124:1213)
Positive stains: CD20, CD79a
References: AJSP 1999;23:1356
In children, 75% male, usually localized disease, no bone marrow involvement, often in nasopharynx, excellent prognosis
Micro: usually centroblast predominant (grade 3 of 3) with high mitotic rate; may have plasmacytoid differentiation
Positive stains: monoclonal light chain expression, bcl6
Negative stains: bcl2
Molecular: usually no bcl2 gene rearrangements, but monoclonal
DD: florid follicular hyperplasia
Common, although only rarely presents as a mass in nasopharynx or nasal cavity
Micro: germinal centers with tingible bodies (macrophages containing apoptotic bodies), mixed inflammatory infiltrate, polyclonal light chains, no atypia
In nasopharynx, lymphocytes may infiltrate overlying epithelium producing lymphoepithelial lesions, but this does NOT indicate lymphoma at this site
EBV positive B cell proliferation associated with exuberant T cell reaction
Associated with immunodeficiency, including HIV
Common sites are lung, kidney, CNS, skin, subcutaneous tissue; rare in nasal area
Among the more common lymphomas of nasopharynx
Micro: sheets of small blue cells with irregular nuclei; overlying mucosa often undisturbed
Positive stains: CD19, CD20, CD5, cyclin D1
Negative stains: CD23
Molecular: t(11;14)
NK / T cell lymphoma, nasal type
Formerly called angiocentric lymphoma, polymorphic reticulosis
Commonly presents as lethal midline granuloma (destructive nasal or midline facial tumor)
Most common lymphoma subtype at this location in Far East and Latin America
Rare in US; patients are often of Asian or Hispanic descent
Highly associated with EBV
5 year survival of 46-63%; commonly relapses to skin or subcutaneous tissue
Case reports: autopsy case of 34 year old Japanese man whose post-radiotherapy lymphocytes were morphologically normal, but EBER1+ by ISH (Archives 2002;126:602); 50 year old HIV+ African man (Archives 2001;125:660)
Gross: usually perforated nasal septum, perforated palate, erosion of antral bone or ulceration of skin overlying nose or antrum
Micro: polymorphic infiltrate of lymphocytes (small to large), plasma cells, neutrophils and scattered atypical lymphoid cells with perinuclear clearing; frequent angiolymphatic invasion and necrosis, although vessel is usually infiltrated by atypical lymphocytes with no neutrophils and no fibrinoid necrosis present; often epitheliotropism; frequent histiocytes with erythrophagocytosis
Treatment: radiotherapy (high relapse rate), chemotherapy (tumors often resistant)
Positive stains: CD2, CD3 (cytoplasmic), EBER-ISH (100%), CD56 (65%); p53 (50%), CD45RO, CD43, TIA1, granzyme B, perforin (35-100%), CD8 (20%), EBV LMP1 (48%)
Negative stains: CD3 (nuclear), CD16 (positive on histiocytes but not tumor cells), CD57; CD79a (usually)
Molecular: no T cell receptor gene rearrangement, no immunoglobulin light or heavy chain rearrangements
DD: Wegener’s granulomatosis, idiopathic midline destructive disease, T cell rich B cell lymphoma (lymphomatoid granulomatosis), Ewing’s sarcoma/PNET (also CD56+), florid HSV infection (HSV+, EBV-, no angioinvasion or angiodestruction, polyclonal, Mod Path 2003;16:166)
References: AJSP 1999;23:1356 (US cases); AJSP 2000;24:1511 (US cases), Hum Path 2004;35:86 (Japanese cases)
Micro: no necrosis, no marked angiolymphatic invasion; often intense squamous hyperplasia proliferating downward from overlying mucosa, but without atypia
Negative stains: CD56
Molecular: clonal rearrangement of T cell receptor gene
Nasal cavity and paranasal sinuses are common site of extramedullary plasmacytoma
May present as soft, bleeding mass
Usually age 40+ years; 80% male
Most patients, even with solitary tumors, develop myeloma up to 10 years later
Treatment: radiation therapy
Micro: monomorphic infiltrate of immature plasma cells; usually no other inflammatory cells
Positive stains: light chain monoclonality, EMA, variable CD45
DD: diffuse large B cell lymphoma with immunoblastic features, lymphoplasmacytic lymphoma (usually disseminated with monoclonal IgM gammopathy, plasma cells and lymphocytes), granulocytic sarcoma (eosinophilic myelocytes, positive chloracetate esterase stain)
Other tumors
Resembles peripheral ameloblastoma of oral cavity
DD: sinonasal extension of craniopharyngioma
Similar to giant cell reparative granuloma, but also has involvement of contiguous bones
15-26% recur
May be associated with fibrous dysplasia
Micro: spindled, ovoid or round histiocytes-like cells in well vascularized fibrous stroma; cells have 1-3 nuclei and may form giant cells with 10-20 nuclei that aggregate in groups of 6-12 cells; giant cells tend to invade and line vascular channels; lesions contain metaplastic woven bone and lamellar bone lined by osteoblasts and occasionally osteoclasts; prominent extravasation of blood, numerous mitotic figures
Very rare in nasal cavity
In contrast to renal tumors, not associated with tuberous sclerosis, usually affects older men, small (up to 4 cm), HMB45 negative Micro: smooth muscle cells, fat cells and blood vessels of various sizes; lymphoid aggregates are present
Positive stains: alpha smooth muscle actin, muscle specific actin, S100 (fat cells)
Negative stains: HMB45 (unlike liver and kidney cases)
References: Archives 1999;123:789
Rare
Usually bleeding and polypoid masses
DD: papillary endothelial hyperplasia