Tài liệu Infectious Diseases of the Head and Neck pptx

Bacterial Infections Bacterial Sinusitis and Tonsillitis Acute and chronic sinus infections are most commonly caused by bacterial organisms, including Streptococcus moniae, Haemophilus i

Infectious Diseases of the Head and Neck

A variety of infectious diseases may involve head

and neck structures These include bacterial, viral,

fungal, and protozoal infections This article describes

the pathologic features of a variety of infectious diseases

that surgical pathologists may encounter in analysis

of tissue specimens from the head and neck area.

Bacterial Infections Bacterial Sinusitis and Tonsillitis

Acute and chronic sinus infections are most commonly

caused by bacterial organisms, including Streptococcus moniae, Haemophilus influenzae, Moraxella catarrhalis, Staphylococcus aureus, other streptococcal strains, and anaer-

pneu-obic bacteria.1-6These infections may manifest acutely and aremost often treated with antibiotics without need for surgery.Immunosuppressed patients are at risk for other bacterial infec-

tions, such as Pseudomonas species ❚Image 1❚ Patients withrepeated infections may develop chronic sinusitis (infections

>12 weeks in duration), which may require surgical tion to open the sinonasal passageways Histologically, thesinonasal mucosa in chronic sinusitis shows chronic inflam-mation, fibrosis, vascular congestion, stromal edema, and cys-tic dilatation of the submucosal glands.4-6Sinusitis with anallergic cause may show numerous eosinophils In addition,there may be basement membrane thickening, goblet cellhyperplasia, and dystrophic calcification.6 True sinonasalinflammatory polyp formation may be observed The bony tis-sue may show reactive changes Histologic changes similar tothose seen in chronic osteomyelitis have been reported.7-9

interven-Although bacteria are considered the cause of chronicsinusitis, the exact mechanism of infection has yet to bedetermined One study suggested that direct invasion of themucosa by the bacterial pathogens may not be the mecha-nism of infection.10In addition, a recent study implicated thenasopharyngeal reflux of gastric acid as a major contributingfactor in the development of chronic sinusitis refractory totherapy.11The presence of bacterial biofilms on sinonasal

mucosa may help explain disease that is refractory to

antibi-otic therapy in many patients.12,13

Acute tonsillitis is usually due to infection by

Streptococcus species.14The disease is characterized by throat

pain and fever Most cases with a bacterial cause are treated

with antibiotics, and surgery is unwarranted Complications

include abscess formation, cellulitis, scarlet fever, acute

rheu-matic fever, and poststreptococcal glomerulonephritis.14

When tonsillitis becomes chronic, there is often hypertrophy

of the tonsillar tissue, which is histologically characterized by

follicular hyperplasia There are controversies about the

bene-fit of examination of routine tonsillar specimens in surgical

pathology.15,16

Cat-Scratch Disease

Cat-scratch disease is a self-limited infection caused by

the gram-negative bacteria Bartonella henselae, the same

organism that causes bacillary angiomatosis (BA).17-21

Cervical lymph nodes are most commonly affected

Symptoms vary from mild to severe and include malaise,

anorexia, and localized lymphadenopathy Most cases are

associated with a cat scratch or bite, but the disease has also

been linked to scratches caused by other animals and foreign

objects.17,18,22 Males are more commonly affected than

females, and disease is almost always identified in patients

younger than 21 years About 3 to 10 days after exposure, a

raised skin lesion develops in the area of inoculation and is

often followed by painful, regional lymphadenopathy, fever,

malaise, anorexia, weight loss, headache, splenomegaly,

pharyngitis, and/or a maculopapular rash.17,18,22 Atypical

features include conjunctivitis, encephalitis, cranial and

peripheral nerve palsies, thrombotic thrombocytopenic pura, osteomyelitis, hepatosplenomegaly, erythematous skindisease, and pneumonia.17,18,23

pur-The clinical differential diagnosis includes most causes ofinfectious lymphadenitis such as mycobacterial infections,lymphogranuloma venereum, tularemia, brucellosis, infec-tious mononucleosis, syphilis, toxoplasmosis, and fungalinfections, as well as sarcoidosis, lymphoma, drug reactions,and collagen vascular diseases

If the clinical picture fits and serologic data are tent, lymph node biopsy is usually not performed, and thepatient is treated for presumed cat-scratch disease If a biopsy

consis-is performed, the lymph node often shows focal areas ofnecrosis with neutrophils surrounding germinal centers

❚Image 2❚ Organisms may be seen within histiocytes and innecrotic areas and thrombosed blood vessels Necrotizinggranulomas and multinucleated giant cells may be seen Thegram-negative organisms are often seen with Warthin-Starrystain or Brown-Hopps modified Gram stain.17Organisms may

be difficult to find because of the background and nonspecificstaining seen with histochemical stains, and additional ancil-lary techniques such as serum titers, immunohistochemicalanalysis, and polymerase chain reaction (PCR) may be usedfor diagnosis.21,24-28

Treatment is usually supportive; however, if the toms are severe, antibiotics may be used The disease usuallylasts 2 to 5 months but may persist for as long as 2 years Thedisease usually resolves without sequelae Although immuno-suppressed patients may be at risk for the development of dis-seminated disease,23,29 antibiotic therapy can eradicate theorganism without sequelae

❚Image 1❚Acute bacterial sinusitis A, Acute necrotizing sinusitis in an immunosuppressed patient with acute lymphocytic leukemia (H&E, ×25) B, Numerous gram-negative bacteria are demonstrated (Gram, ×100) Cultures grew Pseudomonas aeruginosa.

Bacillary Angiomatosis

BA is a systemic disease caused by B henselae and

Bartonella quintana.22The disease, which was first described

in 1983, is usually seen in immunosuppressed people,

especial-ly those infected with HIV, although cases have been reported

in immunocompetent people.22,30-33BA is characterized by the

presence of solitary or multiple, tender, red papular or nodular

skin lesions usually involving the face and extremities

Postmortem examination may show similar lesions involving

the brain, bone, lung, lymph nodes, liver (peliosis hepatis),

spleen, and mucosal and peritoneal surfaces.30,34

There are 4 skin lesions characteristically seen with

BA22,31: (1) nodules resembling lobular capillary hemangioma

(pyogenic granuloma); (2) nodules similar to those seen in

Kaposi sarcoma; (3) dry, scaly, hyperkeratotic plaque lesions;

and (4) subcutaneous nodules More recent studies have also

described the presence of pseudoangiomatous hyperplasia in

patients with BA.35

Although BA and cat-scratch disease are caused by the

same organism,36 the histologic features are quite different

Histologic examination of BA lesions shows ectatic vessels

lined by plump, cuboidal endothelial cells that may show

marked pleomorphism and mitotic activity and, therefore,

may be confused with malignancy22 ❚Image 3A❚ The presence

of neutrophils and fibrin adjacent to blood vessels may aid in

the diagnosis ❚Image 3B❚ The organisms are best observed

with Warthin-Starry stain or Grocott-methenamine silver

stain The diagnosis can be confirmed by

immunohistochemi-cal analysis or PCR-based studies.36-38Similar lesions may be

encountered in the oral mucosa, lymph nodes, liver, spleen,bone marrow, larynx, gastrointestinal tract, peritoneum,diaphragm, lung, and central nervous system.31

Mycobacterial Lymphadenitis

Mycobacterial cervical lymphadenitis is most often seen

in immunocompromised people In adults, more than 90% ofcases of mycobacteria-induced lymphadenitis are due to

❚Image 3❚Bacillary angiomatosis (BA) A, Skin biopsy specimen from an HIV+ male with BA Note the dermal vascular

proliferation with surrounding inflammatory response (H&E, ×25) B, Higher power view of BA in an HIV+ male The vascular

proliferation is characterized by the presence of plump, cuboidal endothelial cells and is surrounded by inflammatory cells, especially neutrophils (H&E, ×100) This finding aids in making the diagnosis of BA Glass slides for photographing provided by Rosalie Elenitsas, MD, Dermatopathology, University of Pennsylvania Medical Center, Philadelphia.

❚Image 2❚ Cat-scratch disease Necrotizing lymphadenitis due

to cat-scratch disease (H&E, ×50) Serology studies confirmed the diagnosis of Bartonella henselae.

Mycobacteria tuberculosis (MTB; scrofula), whereas in

chil-dren, more than 90% of cases are due to atypical

mycobacte-ria.39-41Although the incidence of MTB in the United States is

lower than in other countries, it is increasing owing to

immi-gration from endemic countries and urban crowding

Lymphadenitis is seen in about 5% of immunocompetent

patients infected with MTB, with cervical lymph node

involvement being seen most commonly.39-41

Clinically, patients with scrofula usually seek care

because of a painless enlarging neck mass, fever, chills,

weight loss, and malaise Lymphadenitis usually involves

anterior cervical nodes.40 Nontuberculous mycobacterial

infections usually manifest with a long-standing neck mass

without systemic signs and symptoms.40The clinical

differen-tial diagnosis is quite broad and includes congenital disorders

such as branchial cleft cyst, thyroglossal duct cyst, cystic

hygroma, a variety of infectious diseases, and malignancies

The diagnosis can be made by fine-needle aspiration

(FNA) biopsy with cytologic examination of the biopsy

mate-rial.42-44In addition, the FNA can supply material for culture

and PCR, which may be used to rapidly identify the species of

the mycobacteria.42-45PCR can also be performed on

forma-lin-fixed, paraffin-embedded tissue samples.46,47

Histopathologically, the resected lymph nodes

character-istically show necrotizing granulomas, often associated with

giant cells; however, a variety of histopathologic changes have

been described, including the presence of well-formed

granu-lomas with little necrosis; well-formed granugranu-lomas with

cen-tral necrosis; poorly formed granulomas with a necrotic

back-ground; and a mixed histiocytic, lymphocytic, and neutrophilic

infiltrate with necrosis and without granuloma formation48,49

❚Image 4❚ Organisms may be seen by acid-fast stains such asZiehl-Neelsen, Kinyoun, and auramine O, as well as Dieterlestain.50 However, histopathologic examination cannot effec-tively type mycobacteria, and ancillary studies, such as culture

or PCR, are necessary for accurate species identification.Features that have been used to distinguish nontuberculousmycobacterial lymphadenitis from tuberculous lymphadenitisinclude the presence of microabscesses, ill-defined granulo-mas, noncaseating granulomas, and fewer giant cells in theformer,48,49although culture or molecular testing is still con-sidered the best means for diagnosis

Rhinoscleroma

Rhinoscleroma (“hard nose”) is a chronic, self-limited,granulomatous disease that involves the nasal cavity and otherstructures of the upper respiratory tract The disease is caused

by Klebsiella rhinoscleromatis, a gram-negative organism that

is endemic to Central America, Egypt, Africa, India, andIndonesia51,52and rarely seen in the United States The organ-ism is contracted by direct inhalation of contaminated materi-

al during a prolonged period.51,52The pathogenesis of the ease is basically unknown, but infection is associated withcrowded conditions and poor hygiene

dis-Rhinoscleroma most commonly involves the nasal cavitybut may also affect the larynx, nasopharynx, oral cavity,paranasal sinuses, soft tissues surrounding head and neckstructures, and, rarely, the orbit.51-57Young females are affect-

ed more commonly than are males Clinically, patients haveinflammatory polyps that involve the nasal septum and sparethe sinuses.51,52,58Other features include rhinorrhea, epistaxis,dysphagia, nasal deformities, oral anesthesia, stridor, dyspho-nia, and anosmia.51,52Patients rarely have a Rosai-Dorfmantype of reaction in regional lymph nodes.59

There are 3 stages of rhinoscleroma51,52: (1) the catarrhal

or atrophic stage in which patients have a nonspecific rhinitisthat develops into a purulent nasal discharge with mucosalcrusting; can last weeks to months; (2) the granulomatous orhypertrophic stage in which there is development of nasalpolyps, bleeding, nasal enlargement, and nasal cartilagedestruction; and (3) the sclerotic or fibrotic stage in which theinflammatory changes undergo fibrosis; can result in signifi-cant facial deformities

The diagnosis can be made by culturing the organism;however, only 50% of lesions will be positive.52The diagno-sis can also be made by cytologic examination of smears ofnasal brushing material, which may demonstrate the charac-teristic large, vacuolated Mikulicz cells that are histiocytescontaining the organisms Tissue biopsies also reveal distinc-tive findings In the catarrhal stage, there may be squamousmetaplasia and a nonspecific neutrophil infiltrate along withgranulation tissue In the granulomatous stage, a lymphoplas-macytic infiltrate with Russell bodies, pseudoepitheliomatous

❚Image 4❚ Mycobacterial cervical lymphadenitis Cervical

lymph node showing necrotizing granulomatous inflammation

(H&E, ×50).

hyperplasia of the mucosa, and groups of large vacuolated

his-tiocytes (Mikulicz cells) containing the bacterial organisms

are seen ❚Image 5❚ If numerous, the bacteria can be seen by

H&E staining, but Gram, periodic acid–Schiff (PAS), silver,

or immunohistochemical staining may be required to confirm

the diagnosis.60,61In the sclerotic stage, extensive fibrosis may

lead to stenosis and disfigurement Diagnostic cells may be

difficult to identify in this stage

The differential diagnosis includes other infectious

granulomatous diseases caused by bacteria (eg, tuberculosis,

actinomycosis, syphilis, and leprosy), fungi (eg,

histoplas-mosis, blastomycosis, paracoccidioidomycosis, and

sporotri-chosis), and parasites (eg, mucocutaneous leishmaniasis)

Noninfectious processes to be considered include

inflamma-tory conditions, such as Rosai-Dorfman disease and

Wegener granulomatosis, and neoplastic processes,

particu-larly lymphoma The disease is treated with long-term

antibiotic therapy

Leprosy

Leprosy is a chronic granulomatous disease involving

skin and peripheral nerves that is caused by Mycobacterium

leprae.62,63The disease was described in biblical times, and

the incidence peaked in Europe in the 13th century The

infec-tion usually affects superficial peripheral nerves, skin, mucous

membranes, urinary tract, the eyes, and the testes, and disease

manifestations are a result of the inflammatory reaction to the

organism leading to scarring and deformities Involvement of

the nasal cavity and paranasal sinuses may manifest before the

clinical skin lesions.64

Leprosy is a spectrum of disease ranging from a localized,deforming, self-limited process (tuberculoid leprosy [TL]) tosystemic disease that, left untreated, may be fatal (lepromatousleprosy [LL]).65-67 Between these 2 stages, there are severalborderline forms of the disease (borderline tuberculoid, mid-borderline, and borderline lepromatous) The disease maychange from one stage to another with treatment Treatmentoften moves the disease process toward TL, whereas decreasedimmunosuppression can move borderline or TL toward LL.Most cases of leprosy are concentrated in Brazil, India,Madagascar, Mozambique, and Nepal.61,62,66,67In the UnitedStates, leprosy is rare but is found in parts of Florida,Louisiana, and Texas, areas of New York City, and Asian andMexican communities in California.61,62,66,67

In TL, there is usually a large, ill-defined, numb skinplaque The plaque may be seen anywhere on the skin butoften spares the scalp Spontaneous resolution may takeyears, resulting in scars and depigmentation Progression canalso occur, leading to borderline-type leprosy, and, in rarecases, untreated patients can develop LL TL commonlyinvolves nerves, and patients develop tender, thickenednerves with loss of sensation and motor function In LL, there

is often no sensation loss and there is absence of nerve ening LL can result in nodules or plaques on the skin Eyeinvolvement causes pain, photophobias, decreased visualacuity, glaucoma, and blindness Laryngeal involvementresults in stridor and hoarseness Nasal disease can cause asaddle-nose deformity, and nasal endoscopy has become away in which patients can be followed up.64LL cannot revert

thick-to less severe forms of the disease

❚Image 5❚Rhinoscleroma A, Florid phase of rhinoscleroma in a 25-year-old woman Note the presence of a mixed inflammatory

cell infiltrate consisting of lymphocytes, plasma cells, and neutrophils, as well as the presence of histiocytes with clear

cytoplasm (Mikulicz cells) (H&E, ×50) B, Higher power view of Mikulicz cells in the florid phase of rhinoscleroma (H&E, ×100).

The infection is most easily diagnosed in this phase of the disease.

The diagnosis may require skin or nerve biopsy.

Histologic findings vary according to the type of leprosy.62In

TL, noncaseating granulomas that destroy dermal nerves are

present Skin appendages are lost, and organisms are difficult

to identify ❚Image 6A❚and ❚Image 6B❚ In LL, the epidermis is

normal, and a Grenz zone separates the epidermis from a

dif-fuse dermal inflammatory reaction consisting of macrophages,

foamy histiocytes (Virchow, or lepra, cells), and many

intracel-lular organisms ❚Image 6C❚, ❚Image 6D❚, ❚Image 6E❚, and

❚Image 6F❚ Epithelioid cells and giant cells are not found

Inflammation is most prominent around blood vessels, nerves,

and skin appendages, but dermal nerve structure is preserved

Assays have been developed for demonstration of M

lep-rae–specific DNA and ribosomal RNA (rRNA) sequences in

various specimens such as nasal smears, skin, and blood

PCR for bacterial DNA is most sensitive and can detect fewer

than 10 organisms.68,69The majority of patients with suspected

leprosy who have negative screening smears have positive

PCR results In situ hybridization can be used to establish the

diagnosis if necessary.69,70

With early diagnosis and treatment, progression of

dis-ease can be limited, but recovery of neuronal function is

vari-able.66,67Much of the chronic changes result from repeated

trauma to numb extremities Even when disease is controlled,

the stigma and social isolation often persist

Gonorrhea

Gonorrhea is a sexually transmitted disease caused by

Neisseria gonorrhoeae Infection may affect almost any

mucous membrane In the head and neck, the most commonlyinvolved areas include the pharynx and the conjunctiva.71,72Asignificant number of patients have pharyngitis, which usually

is asymptomatic but may cause discomfort that can be severe.Conjunctivitis can occur in adults and in children followingdirect inoculation and can lead to blindness In neonates, bilat-eral conjunctivitis often follows vaginal delivery by an infectedmother Blindness from neonatal gonococcal infection is a seri-ous problem in developing countries but is uncommon in theUnited States where prophylaxis during the neonatal period iscommon Prognosis is excellent if therapy is initiated promptly

Syphilis

Syphilis is a sexually transmitted infectious disease

caused by the spirochete Treponema pallidum It is almost

always transmitted by sexual contact with infectious lesions,but it also can be transmitted in utero and through blood trans-fusion.73 T pallidum penetrates abraded skin and intact

mucous membranes and rapidly disseminates through thelymphoreticular system

The initial lesion of syphilis develops at the sion site about 10 to 90 days after exposure and then heals

❚Image 6❚Leprosy A, Low-power view of tuberculoid leprosy (TL) showing a superficial and deep dermal inflammatory infiltrate consisting of granulomas (H&E, ×5) B, Higher power view of TL showing multiple granulomas (H&E, ×50) In this form of leprosy, there is nerve destruction by the granulomatous disease Only rare organisms are seen in tissue sections C, Low- power view of lepromatous leprosy (LL) showing a superficial and deep dermal inflammatory infiltrate (H&E, ×12.5) D and E, Higher power view of LL showing numerous histiocytes with clear cytoplasm (Virchow, or lepra, cells) (D, H&E, ×100; E, H&E,

×100) This form of leprosy spares nerves and rarely shows granulomas F, Tissue stain showing acid-fast bacillus (AFB)-positive

organisms in a patient with LL confirmed by culture (AFB, ×315) Glass slides for photographing provided by Rosalie Elenitsas,

MD, Dermatopathology, University of Pennsylvania Medical Center, Philadelphia.

spontaneously in 3 to 7 weeks Secondary syphilis develops

about 4 to 10 weeks after the appearance of the primary

lesion.73Patients often complain of malaise, fever, myalgias,

and arthralgias Physical examination may reveal

lym-phadenopathy and a maculopapular rash Secondary syphilis

usually resolves without treatment and becomes latent In

about 30% of patients in the latent stage, tertiary syphilis will

develop, which may affect the heart and nervous system.73

All stages of syphilis may manifest with head and neck

findings.74-78The chancre sore of primary syphilis can involve

oral mucosa.74-78Patients with secondary syphilis may have

mucosal erosions on the tongue, lips, and oral mucosa.74-78

Patients may also have hairy leukoplakia, oral lichen planus,

oral erythema multiforme, alopecia, sore throat, headache,

stiff neck pain, and optic neuritis Gummatous lesions of

ter-tiary syphilis may involve mucous membranes, and in patients

with neurosyphilis, meningitis and dementia may develop

Oral lesions in primary and secondary syphilis are cific and characterized by squamous hyperplasia and a plasmacell infiltrate that extends deep into the submucosa.74-78

nonspe-Although these findings are nonspecific, the presence of amarked, deeply infiltrating plasma cell infiltrate should alertpathologists to the possibility of syphilis Neuritis has also beendescribed in primary and secondary disease Mucosal ischemicchanges due to obliterative endarteritis may also be seen.Tertiary syphilis involving the oral cavity may also show achronic inflammatory infiltrate with few plasma cells.74-78

Propionibacterium propionicum Actinomycosis is

character-ized by a suppurative and granulomatous inflammatory reaction

and formation of multiple abscesses and sinus tracts

Cervicofacial actinomycosis is the most common manifestation

of infection.79-84

Patients with cervicofacial disease usually report a history of

dental surgery, oral trauma, poor hygiene, or periodontal disease

and painless soft tissue swelling involving the submandibular

area Long-standing infection may be associated with multiple

sinus tracts that have a tendency to heal and recur Patients have a

nodular mass at the angle of the jaw The masses gradually

increase in size and number and form sinuses that open onto the

face and neck Although infection is often seen in the jaw area,

Actinomyces infections have been described in other sites,

includ-ing the sinuses, mastoid, major salivary glands, and thyroid.85-92

Histologically, infection is characterized by a mixed

suppurative and granulomatous inflammatory reaction

“Sulfur granules” are for the most part pathognomonic forinfection and can be found in the lesions and in the sinusdrainage ❚Image 7A❚ and ❚Image 7B❚ The granules areapproximately 1 mm in diameter and can be seen by thenaked eye as yellowish particles Microscopically, the parti-cles are shown to consist of filamentous bacteria surrounded

by neutrophils Gram stain reveals gram-positive, branchingfilaments, with radially arranged hyphae

Treatment with antibiotics can eradicate the infection;however, surgery may be necessary for proper drainage.Death may occur with infections that cannot be controlledwith antibiotics or surgery

Anthrax

Bacillus anthracis is an aerobic, spore-forming,

gram-positive bacillus The organism has received worldwideattention because of its potential for use as a bioterrorism

C ❚Image 7❚Actinomyces infection A, Mandibular bone in a

patient after radiation therapy for parotid gland mucoepidermoid carcinoma in whom a necrotic mandible showed Actinomyces osteomyelitis (H&E, ×100) B, Gram stain highlights the filamentous Actinomyces organisms

(×100) C, Grocott silver stain also highlights the Actinomyces

organisms (×100).

weapon There are 3 major forms of infection with the

organism: cutaneous, inhalation, and gastrointestinal.93The

details of these forms of anthrax will not be discussed with

the exception of gastrointestinal anthrax, which may

mani-fest with a localized oropharyngeal lesion that most likely is

a result of colonization of the oropharyngeal mucosa by the

organisms It is believed that the organism gains entrance

into the mucosa through abrasions or possibly by

spore-con-taminated food products Localized ulcers, cervical

lym-phadenopathy, and localized edema may develop

Histologically, the lesions show hemorrhage, edema, and

necrosis with a neutrophilic infiltrate.93 Lymph nodes can

show extensive necrosis and hemorrhage with the presence

of gram-positive, boxcar-shaped, and encapsulated

bacte-ria93 ❚Image 8❚ The organism can be cultured, and

immuno-stains can be used to identify the organism in smears and

tissue sections.94

Fungal Diseases

A variety of fungal infections can result in head and neckmanifestations Head and neck fungal infections have beenassociated with mucosal ulceration and erosion, lym-phadenopathy, and sinonasal disease This section will notdetail all types of fungal infections but will concentrate onsinonasal fungal disease

Sinonasal Fungal Disease

Sinonasal fungal disease was initially described in the1600s; however, only recently has this topic become of greatinterest There are 4 types of sinonasal fungal disease: (1)chronic indolent invasive sinusitis, (2) fulminant fungal sinusi-tis, (3) fungus ball, and (4) allergic fungal sinusitis (AFS).95-99

Chronic indolent invasive fungal sinusitis is of 2 types:chronic invasive granulomatous sinusitis and chronic invasivefungal sinusitis.95-99Chronic granulomatous sinusitis is seen in

❚Image 8❚Anthrax A, Lymph node in a patient with

disseminated Bacillus anthracis at autopsy (H&E, ×50) Note the extensive hemorrhagic necrosis of the node This picture is typical for B anthracis infection B, B anthracis in a lymph node

in the case mentioned in A (Giemsa, ×100) C, B anthracis.

The organisms are gram-positive, long slender rods (Gram,

×250) Photographs courtesy of Centers for Disease Control and Prevention/Marshall Fox, MD, via the Public Health Image Library.

C

immunocompetent patients, usually in northern India, Sudan,

and North Africa The most common causative fungal organism

is Aspergillus flavus Patients have proptosis caused by a

granu-lomatous reaction to the fungus Treatment includes surgical

debridement followed by antifungal therapy Chronic invasive

fungal sinusitis is a slowly progressive, low-grade, invasive

fun-gal infection that usually occurs in patients with diabetes

Patients have symptoms of long-standing sinusitis and are

usual-ly not in acute distress Chronic invasive fungal sinusitis is most

commonly associated with Aspergillus fumigatus Treatment

consists of surgery followed by systemic antifungal therapy

Fulminant (angioinvasive) fungal sinusitis is often seen in

immunosuppressed patients, particularly patients with

hema-tologic malignancies and diabetes, although occasionally the

disease may develop in immunocompetent patients.95-99The

patients get infected with the fungus, and subsequently tissue

and vascular invasion with massive necrosis develop,

necessi-tating surgery and antifungal therapy ❚Image 9❚ Patients have

fever, cough, nasal discharge, and mental status changes The

organisms usually implicated are Aspergillus species and

organisms in the Mucorales order (Rhizopus, Rhizomucor,

Absidia, Mucor, Cunninghamella, Mortierella, Saksenaea,

and Apophysomyces).95-99Treatment includes emergency

sur-gery with sinus debridement and intravenous antifungal

ther-apy Despite therapy, the prognosis is poor

A fungus ball is a tangled mass of fungus (most

common-ly A flavus or A fumigatus) in the sinonasal tract (most

com-monly the maxillary sinus) associated with minimal if any

inflammatory reaction.95-102 Patients are usually healthy and

nonatopic and have unilateral sinonasal blockage and pain and

are treated with surgical debridement alone The fungus may be

related to a history of trauma or surgery Histologically, thespecimen consists of a mass of fungal organisms Littleinflammatory reaction is present ❚Image 10❚ Although thedisease is usually indolent, reports have demonstrated thatthese lesions may develop into acute fulminant sinusitis inpreviously healthy patients who become immunosuppressed.103

AFS occurs in immunocompetent patients with nasalpolyps, atopy, and asthma in whom an allergic immuneresponse develops to extramucosal fungal antigens.95-99,104-111

The disease was first described in 1983 by Katzenstein et al,104

who presented a series of patients who had allergic symptoms,sinonasal contents with a histologic picture similar to that seen

in allergic bronchopulmonary aspergillosis, and the presence

of fungi histologically compatible with Aspergillus Since that

time, several fungi have been implicated in the pathogenesis

of this disease entity.112-114AFS represents approximately 10%

of all chronic sinusitis cases requiring surgery Studies have cated that AFS may be more common than previously thought

indi-A group from the Mayo Clinic grew fungal organisms in ing specimens from 96% of patients with chronic sinusitis.115

wash-However, this study has been criticized because the patients maynot have fulfilled the diagnostic criteria for AFS.116

AFS can be seen in patients of any age or sex, and the nosis is suspected based on clinical manifestations and charac-teristic computed tomography scan or magnetic resonance imag-ing findings.95-99,104-111,117Patients may have facial deformitiesand visual loss The diagnosis is confirmed by histologic exam-ination of the sinus contents for the presence of “allergic mucin.”Fungal cultures and allergy testing may support the diagnosis.Although the pathogenesis of AFS is not entirely under-stood, AFS is considered to represent a hypersensitivity reaction

❚Image 9❚Angioinvasive fungal sinusitis A, Sinonasal mucosa biopsy specimen in an immunosuppressed patient after

treatment for acute lymphocytic leukemia There is extensive necrosis due to angioinvasive fungal infection histologically consistent with Aspergillus (H&E, ×25) B, Grocott silver stain confirms the presence of angioinvasive fungus (×50).

to fungal organisms that have colonized the sinonasal tract but

have not invaded surrounding tissues.118,119Predisposing

fac-tors for disease development include anatomic abnormalities

such as nasal polyps and nasal septum deviation and foreign

bodies As a result of obstruction in the nasal cavity, the host

cannot easily remove inhaled fungi Fungi may then

repro-duce and, if the patient is predisposed, may incite an allergic

reaction It is believed that a complex immunologic reaction

involving type I and type III responses ensues, resulting in

mucosal edema, influx of eosinophils, and obstruction

pro-moting further antigen contact with sensitized mast cells As

the eosinophils degranulate, they release major basic protein,

which can cause tissue necrosis

At gross examination, the sinus contents from patients with

AFS are often described as peanut butter–like, inspissated

mucus material that is usually green, brown, or grayish

Microscopic examination of this material should show allergic

mucin that contains mucinous material with sloughed epithelial

cells, numerous eosinophils, Charcot-Leyden crystals, and

other inflammatory cells arranged in a laminar pattern and

associated with scattered fungal hyphae ❚Image 11❚ Silver or

PAS stains highlight the fungi, which can be fragmented,

dilat-ed, or distorted In addition, the Fontana-Masson melanin stain

can be useful because dematiaceous fungi and Aspergillus

niger (which have pigment similar to melanin) are highlighted

with this stain whereas other fungi are not Fungal hyphae are

often rare and may be missed if all mucinous material is not

submitted for review It should be realized that any sinonasal

chronic inflammatory or allergic sinus process may have a

fun-gal cause even without histopathologic identification of fungus

Allergic mucin has been described in patients without evidence

of fungal infection This has been termed eosinophilic nous rhinosinusitis and suggests that allergic mucin may be aresponse to another allergen.120-122

muci-When positive, cultures from patients with AFS most often

grow dematiaceous fungi (Bipolaris, Curvularia, Exserohilum, Alternaria, Cladosporium, and Scedosporium) or Aspergillus.112-114

A study using in situ hybridization found that more than 50% of

patients with AFS harbored Aspergillus or Penicillium rRNA.123

The type of fungi isolated may vary with the area of the country.The diagnosis of AFS should be considered in patientswith nasal polyps, atopy, and refractory chronic sinusitis and

is suggested by characteristic computed tomography scanfindings, including rounded soft tissue masses, polypoid nasalmucosal thickening, bony remodeling, and/or expansion of thenasal cavity or paranasal sinuses.105,106,110,116,118 Becausesome patients may show only local mucosal allergy, the diag-nosis of allergic disease should be thoroughly sought inpatients who have a clinical history suggesting allergic diseasedespite negative skin and serologic test results

Surgery is used to establish diagnosis and for treatment.The aim of surgery in AFS is to reduce fungal burden and torestore normal sinus drainage and ventilation Medical thera-

py includes nasal steroids and, sometimes, oral steroid

thera-py, especially for patients with recurrent, aggressive AFS andsevere atopy Antifungal therapy is not used

Viral Infections and Virally Related Diseases

A variety of viral and virally related diseases show headand neck manifestations Viruses are associated not only with

B A

❚Image 10❚Fungus ball A, Fungus ball removed from the sinonasal tract of an immunocompetent patient The histologic

features are characterized by the presence of an entangled mass of fungal organisms with minimal surrounding inflammatory

reaction (H&E, ×25) B, Fungus ball with pigmented fungal forms suggestive of dematiaceous fungi (H&E, ×50).

inflammatory or nonspecific systemic conditions but also

with neoplasias

Tonsillitis and Oropharyngitis/Parotitis

Acute tonsillitis and oropharyngitis are frequently

caused by viruses Viral causes of tonsillitis include

Epstein-Barr virus (EBV), herpes simplex virus (HSV),

parainfluenza virus, measles virus, coxsackievirus, and

ade-novirus Paramyxovirus (mumps virus) infects the parotid

and submandibular gland, resulting in salivary gland

enlargement Detailed pathologic changes of these

infec-tions will not be discussed

Molluscum Contagiosum

Molluscum contagiosum is a DNA poxvirus that can

pro-duce cutaneous infection almost anywhere, including the head

and neck area, particularly the face.124,125The infection results in

umbilicated papules on the skin and is spread by close contact

The disease is self-limited in immunocompetent patients;

how-ever, the virus can disseminate and kill immunosuppressed

patients.126-128 Infection is commonly seen in children and

may be more frequently seen in patients with allergic

dermati-tis.124,125Oral infection is commonly seen in

immunocompro-mised patients.126-128 The histologic feature of molluscum

infection is the presence of basophilic intracytoplasmic

inclusions in infected cells of the skin These are often

referred to as Henderson-Patterson bodies and are

pathogno-monic for infection124 ❚Image 12❚ In early infection, the

virus is present in hair follicles and eccrine ducts but over

time spreads upward, resulting in central umbilication of the

lesion and extrusion of the virus onto the skin surface.124,125

In situ hybridization has been used to localize infected cells,but this test is usually not needed for diagnosis because thehistopathologic findings are so classic.129As mentioned, thedisease is usually self-limited, but untreated ocular involve-ment can lead to scarring and pain in infected children

HIV

Infection with HIV (an RNA Lentivirus) can manifest inseveral ways in the head and neck area Many of theselesions have been (or will be) discussed separately Almost70% of HIV-infected patients will have lesions involving thehead and neck.130-136Sinusitis, mucosal ulceration, candidi-asis, Kaposi sarcoma (KS), salivary gland enlargement, lym-phadenopathy, chronic sinusitis, and many other entities may

be seen It is believed that the incidence of head and necklesions associated with HIV has been decreasing with antivi-ral therapy.131,132

Oral Mucosal and Sinonasal Lesions

Mucosal ulcerations are commonly identified in HIV+patients.130,132,133,136These ulcerations may be due to infec-tions with viruses, bacteria, or fungus In addition, painful,aphthous ulcers of unknown cause may occur on the muco-sal surfaces of the oropharynx ❚Image 13❚ Another form ofulceration is that associated with neutropenia This type ofulcer is seen in patients with neutrophil counts less than800/µL (0.8 × 109/L) Like the aphthous ulcers, the cause isunknown HIV+ patients have an increased incidence of den-tal caries, which is believed to be from xerostomia due to

❚Image 11❚Allergic fungal sinusitis (AFS) A, Allergic mucin (H&E, ×50) Allergic mucin consists of mucinous material admixed

with inflammatory cells including neutrophils and eosinophils The presence of allergic mucin in a sinonasal specimen should

alert pathologists to the possibility of AFS B, The fungi in the allergic mucin can be identified with H&E staining (×100) without

additional special stains in some but not in most cases.

anti-HIV medications as well as from lymphoid hyperplasia

with duct blockage in salivary glands.130,132,135,136

For unknown reasons, allergic rhinitis and chronic

sinusi-tis are more common in HIV+ patients.131-135 In early HIV

infection, sinusitis is usually due to the same organisms that

cause sinusitis in immunocompetent hosts.133 The sinusitis

seen in HIV+ patients is usually more severe than in

non-HIV+ patients and often does not respond to antibiotic

thera-py In later stages, the infectious agents are more likely to be

viruses, fungi, and, rarely, bacteria such as Pseudomonas

aeruginosa.134Neoplasms that may be seen in HIV+ patients

include squamous cell carcinoma, KS, and lymphoma

Lymphoid Hypertrophy

In early HIV infection, there is often persistent cervical

lymphadenopathy Pathologically, the enlarged lymph

nodes show reactive hyperplasia with follicular expansion

and loss of mantle zones There is often paracortical

expan-sion with increased immunoblasts, plasma cells, and

vascu-lar proliferation and multinucleated giant cells, especially

early in the infection.137-139Other causes of

lymphadenopa-thy in HIV+ patients include infection (BA and infections

caused by mycobacteria, Cryptococcus, Histoplasma, and

Pneumocystis carinii) and neoplasms (KS, lymphoma, and

metastatic carcinoma)

In the sinonasal tract and the oropharynx, patients with

HIV infection may show prominent lymphoid hypertrophy

of tonsillar tissue and the adenoids.130,132,133-135

Nasopharyngeal lymphoid hypertrophy is often seen in the

early stages of HIV infection.133Usually this hypertrophy is

symmetric; however, if it is bulky and asymmetric, biopsy

may be warranted to rule out the possibility of lymphoma

Tonsil and adenoid hypertrophy may lead to dysphagia,sleep apnea, and breathing difficulties

Parotid Enlargement

Many HIV+ patients show parotid gland enlargement.This enlargement can be due to reactive changes within intra-parotid lymph nodes, malignant lymphoma, or the develop-ment of benign lymphoepithelial cysts The benign lymphoep-ithelial cysts are often multiloculated and most likely result

from metaplastic and cystic changes within reactive lymph

nodes131-135,140-142 ❚Image 14❚ When first described, the

man-agement of these cysts was considered to be surgical excision,

but owing to their benign nature, more conservative

manage-ment with the use of FNA biopsy to confirm diagnosis has

been advocated A benign lymphoepithelial cyst is an entity

strongly associated with HIV infection, and its presence in an

otherwise healthy host should alert the clinician to do further

testing for HIV

Cutaneous Lesions

Several skin lesions are seen more frequently in HIV+

patients These include KS, BA, seborrheic dermatitis,

psoria-sis, viral infections, pruritic papular eruptions, eosinophilic

folliculitis, and cutaneous carcinomas (squamous cell

carcino-ma and basal cell carcinocarcino-ma).30,143,144

Herpesviruses

Herpesviruses can cause significant pathology in the

head and neck area Primary herpesvirus infections are often

followed by the development of latent viral infections in a

variety of organ systems HSV, cytomegalovirus (CMV),

varicella zoster virus (VZV), EBV, and human herpesvirus

(HHV)-6, HHV-7, and HHV-8 can have manifestations in the

head and neck

HSV-1 and HSV-2

Infection with HSVs may result in significant head and

neck manifestations The severity seems to depend on the

immune state of the infected person Immunosuppressed

patients are at risk for disseminated disease Following mary infection, the virus may become latent in neural tissues,particularly dorsal root ganglion, spinal cord, sympatheticganglion, and peripheral nerves

pri-Acute Herpetic Gingivostomatitis

Acute herpetic gingivostomatitis is the most common ifestation of primary HSV-1 infection in young children.145-149

man-The virus is transmitted by saliva from an infected adult or child,and the incubation period is from days to weeks Clinically, thechild has high fever, irritability, and inability to eat or drink.Findings include severe gingivitis and vesicular lesions on thetongue, buccal mucosa, and palate with extension to the lips andface Reactive cervical adenopathy may be evident The diseaselasts between 3 days and 3 weeks, and patients may still remaininfectious for days to weeks after symptoms have disappeared

Acute Herpetic Pharyngotonsillitis

Acute herpetic pharyngotonsillitis is usually seen in lescents and adults infected with HSV-1 for the first time.Instead of gingivostomatitis as seen in children, patients havepharyngotonsillitis.145,147,148 Clinically, patients have fever,malaise, odynophagia, and headache Vesiculoulcerative lesionsdevelop on the tonsils Primary HSV-2 infection may show sim-ilar findings following infection by orogenital contact

ado-Recurrent Orolabial Herpetic Infection (Herpes Labialis)

Once HSV infection has occurred, the virus often enters

a latent state Reactivation of the viral infection, especiallyHSV-1, results in herpes labialis Reactivation may be associ-ated with other illnesses, trauma, or even sun exposure.Patients have vesicles involving the mouth and lips There isoften a prodrome of pain, tingling, burning, or itching

Ocular HSV Infection

HSV can also cause keratoconjunctivitis Patients haveacute pain, tearing, itching, and swelling Rarely, retinalnecrosis can develop, which can lead to blindness.150,151

HSV Diagnosis

The diagnosis of HSV infection can be made by the ical manifestations in many cases If necessary, a Tzancksmear to look for herpesvirus cytopathic effect may be useful.This preparation cannot differentiate among HSV-1, HSV-2,and VZV, which all produce similar cytologic changes.HSV usually infects squamous epithelial cells, althoughother cell types can be infected The infected cells may under-

clin-go amitotic division, resulting in the formation of ated giant cells The nuclei of HSV-infected cells demonstrateeosinophilic intranuclear inclusions (Cowdry type A) andmarginated nuclear chromatin (“ground-glass” nuclei)

multinucle-❚Image 15❚ Treatment is usually with acyclovir, which can be

❚Image 14❚ Benign lymphoepithelial cyst in an HIV+ male

(H&E, ×25) These cysts are benign and may be a presenting

symptom for HIV infection.

used to treat the outbreak and for prophylaxis to avoid

repeat-ed bouts of disease

Cytomegalovirus

CMV infection may result in head and neck

manifesta-tions, including extensive mucosal ulceration, especially in the

oropharynx and the sinonasal tract.152-154 Patients have sore

throat, odynophagia, and dysphagia Oftentimes, the symptoms

overlap with those seen in infectious mononucleosis Clinicallysignificant infections are seen more frequently in immunosup-pressed patients Retinitis is also a known result of CMV infec-tion155-157 ❚Image 16A❚ Other head and neck sites that may beinvolved by CMV include the parotid, larynx, and thyroid158-160

❚Image 16B❚.The diagnosis of CMV includes tests for serum CMV anti-gens, qualitative and quantitative PCR assays on blood and tissue

samples, and shell vial assays The hallmark of CMV infection

is the finding of intranuclear inclusions consistent with

her-pesvirus infection The cells are often significantly enlarged and

show nuclear and cytoplasmic inclusions CMV infection may

be confirmed by using in situ hybridization or

immunohisto-chemical analysis Treatment includes the use of ganciclovir

Varicella Zoster Virus

VZV is a herpesvirus that causes chickenpox and herpes

zoster (shingles) The virus often manifests in the head and

neck area, especially following primary infection After the

ini-tial infection, VZV enters the dorsal root ganglia and spinal

cord, where it remains latent for the lifetime of the person

Herpes zoster results when the virus becomes reactivated If

the virus becomes latent in the geniculate ganglion,

reactiva-tion may lead to Ramsay Hunt syndrome, which is

character-ized by peripheral facial palsy, pain in the ear and face, and

vesicles in the external ear canal.161,162Reactivation of virusinvolving the ophthalmic division of the trigeminal nerve canresults in herpes ophthalmicus.161,162Patients will have con-junctivitis or corneal ulcers, and complications include blind-ness In some cases of herpes ophthalmicus, the virus willmigrate along the intracranial branches of the trigeminal nerve,causing vascular thrombosis resulting in paralysis.161,162

The Tzanck preparation can be used to identify viralinclusions as in HSV infection Cytologic and histologicexamination of the VZV vesicles will not differentiate VZVfrom HSV infection ❚Image 17❚ Intranuclear eosinophilicinclusions and ground-glass nuclear changes are seen inepithelial cells in both infections Leukocytoclastic vasculitisand hemorrhage are more common in VZV lesions than inherpes simplex Immunohistochemical, in situ hybridization,and PCR techniques on tissue samples can be used to differ-entiate VZV from HSV

C ❚Image 17❚Varicella zoster (VZV) A, Skin biopsy specimen from

a patient with a vesicle on the face (H&E, ×25) B, Higher

power view demonstrating herpetic-type viral inclusions (H&E,

×100) Histologically, VZV and herpes simplex virus (HSV) are

similar C, Immunohistochemical stain for VZV (left,

diaminobenzidine/hematoxylin counterstain, ×100) demonstrates reactivity for the viral capsid antigen, whereas immunohistochemical staining for HSV is negative (right, diaminobenzidine/hematoxylin counterstain, ×100).