Tài liệu Infectious Diseases of the Head and Neck pptx

Microbiology and Infectious Disease / HEAD AND NECK INFECTIONS

Infectious Diseases of the Head and Neck
A Review
Kathleen T. Montone, MD
Key Words: Infectious diseases; Head and neck; Bacteria; Fungus; Protozoa; Virus
DOI: 10.1309/6BBT12WGNK77N4EH

Abstract
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 pneumoniae, Haemophilus influenzae, Moraxella catarrhalis,
Staphylococcus aureus, other streptococcal strains, and anaerobic bacteria.1-6 These infections may manifest acutely and are
most often treated with antibiotics without need for surgery.
Immunosuppressed patients are at risk for other bacterial infections, such as Pseudomonas species ❚Image 1❚. Patients with
repeated infections may develop chronic sinusitis (infections
>12 weeks in duration), which may require surgical intervention to open the sinonasal passageways. Histologically, the
sinonasal mucosa in chronic sinusitis shows chronic inflammation, fibrosis, vascular congestion, stromal edema, and cystic dilatation of the submucosal glands.4-6 Sinusitis with an
allergic cause may show numerous eosinophils. In addition,
there may be basement membrane thickening, goblet cell
hyperplasia, and dystrophic calcification.6 True sinonasal
inflammatory polyp formation may be observed. The bony tissue may show reactive changes. Histologic changes similar to
those seen in chronic osteomyelitis have been reported.7-9

Although bacteria are considered the cause of chronic
sinusitis, the exact mechanism of infection has yet to be
determined. One study suggested that direct invasion of the
mucosa by the bacterial pathogens may not be the mechanism of infection.10 In addition, a recent study implicated the
nasopharyngeal reflux of gastric acid as a major contributing
factor in the development of chronic sinusitis refractory to
therapy.11 The presence of bacterial biofilms on sinonasal
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A

B

❚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.

mucosa may help explain disease that is refractory to antibiotic therapy in many patients.12,13
Acute tonsillitis is usually due to infection by
Streptococcus species.14 The 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 rheumatic 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 benefit 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
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peripheral nerve palsies, thrombotic thrombocytopenic purpura, osteomyelitis, hepatosplenomegaly, erythematous skin
disease, and pneumonia.17,18,23
The clinical differential diagnosis includes most causes of
infectious lymphadenitis such as mycobacterial infections,
lymphogranuloma venereum, tularemia, brucellosis, infectious mononucleosis, syphilis, toxoplasmosis, and fungal
infections, as well as sarcoidosis, lymphoma, drug reactions,
and collagen vascular diseases.
If the clinical picture fits and serologic data are consistent, lymph node biopsy is usually not performed, and the
patient is treated for presumed cat-scratch disease. If a biopsy
is performed, the lymph node often shows focal areas of
necrosis with neutrophils surrounding germinal centers
❚Image 2❚. Organisms may be seen within histiocytes and in
necrotic areas and thrombosed blood vessels. Necrotizing
granulomas and multinucleated giant cells may be seen. The
gram-negative organisms are often seen with Warthin-Starry
stain or Brown-Hopps modified Gram stain.17 Organisms may
be difficult to find because of the background and nonspecific
staining seen with histochemical stains, and additional ancillary techniques such as serum titers, immunohistochemical
analysis, and polymerase chain reaction (PCR) may be used
for diagnosis.21,24-28
Treatment is usually supportive; however, if the symptoms are severe, antibiotics may be used. The disease usually
lasts 2 to 5 months but may persist for as long as 2 years. The
disease usually resolves without sequelae. Although immunosuppressed patients may be at risk for the development of disseminated disease,23,29 antibiotic therapy can eradicate the
organism without sequelae.
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Bacillary Angiomatosis

BA is a systemic disease caused by B henselae and
Bartonella quintana.22 The disease, which was first described
in 1983, is usually seen in immunosuppressed people, especially those infected with HIV, although cases have been reported
in immunocompetent people.22,30-33 BA 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 immunohistochemical analysis or PCR-based studies.36-38 Similar lesions may be

A

❚Image 2❚ Cat-scratch disease. Necrotizing lymphadenitis due

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

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% of
cases of mycobacteria-induced lymphadenitis are due to

B

❚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.

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Mycobacteria tuberculosis (MTB; scrofula), whereas in children, more than 90% of cases are due to atypical mycobacteria.39-41 Although the incidence of MTB in the United States is
lower than in other countries, it is increasing owing to immigration 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.40 The clinical differential 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 material.42-44 In addition, the FNA can supply material for culture
and PCR, which may be used to rapidly identify the species of
the mycobacteria.42-45 PCR can also be performed on formalin-fixed, paraffin-embedded tissue samples.46,47
Histopathologically, the resected lymph nodes characteristically show necrotizing granulomas, often associated with
giant cells; however, a variety of histopathologic changes have
been described, including the presence of well-formed granulomas with little necrosis; well-formed granulomas with central necrosis; poorly formed granulomas with a necrotic background; and a mixed histiocytic, lymphocytic, and neutrophilic
infiltrate with necrosis and without granuloma formation48,49

❚Image 4❚ Mycobacterial cervical lymphadenitis. Cervical
lymph node showing necrotizing granulomatous inflammation
(H&E, ×50).

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❚Image 4❚. Organisms may be seen by acid-fast stains such as

Ziehl-Neelsen, Kinyoun, and auramine O, as well as Dieterle
stain.50 However, histopathologic examination cannot effectively type mycobacteria, and ancillary studies, such as culture
or PCR, are necessary for accurate species identification.
Features that have been used to distinguish nontuberculous
mycobacterial lymphadenitis from tuberculous lymphadenitis
include the presence of microabscesses, ill-defined granulomas, noncaseating granulomas, and fewer giant cells in the
former,48,49 although culture or molecular testing is still considered the best means for diagnosis.
Rhinoscleroma
Rhinoscleroma (“hard nose”) is a chronic, self-limited,
granulomatous disease that involves the nasal cavity and other
structures 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, and
Indonesia51,52 and rarely seen in the United States. The organism is contracted by direct inhalation of contaminated material during a prolonged period.51,52 The pathogenesis of the disease is basically unknown, but infection is associated with
crowded conditions and poor hygiene.
Rhinoscleroma most commonly involves the nasal cavity
but may also affect the larynx, nasopharynx, oral cavity,
paranasal sinuses, soft tissues surrounding head and neck
structures, and, rarely, the orbit.51-57 Young females are affected more commonly than are males. Clinically, patients have
inflammatory polyps that involve the nasal septum and spare
the sinuses.51,52,58 Other features include rhinorrhea, epistaxis,
dysphagia, nasal deformities, oral anesthesia, stridor, dysphonia, and anosmia.51,52 Patients rarely have a Rosai-Dorfman
type 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 rhinitis
that develops into a purulent nasal discharge with mucosal
crusting; can last weeks to months; (2) the granulomatous or
hypertrophic stage in which there is development of nasal
polyps, bleeding, nasal enlargement, and nasal cartilage
destruction; and (3) the sclerotic or fibrotic stage in which the
inflammatory changes undergo fibrosis; can result in significant facial deformities.
The diagnosis can be made by culturing the organism;
however, only 50% of lesions will be positive.52 The diagnosis can also be made by cytologic examination of smears of
nasal brushing material, which may demonstrate the characteristic large, vacuolated Mikulicz cells that are histiocytes
containing the organisms. Tissue biopsies also reveal distinctive findings. In the catarrhal stage, there may be squamous
metaplasia and a nonspecific neutrophil infiltrate along with
granulation tissue. In the granulomatous stage, a lymphoplasmacytic infiltrate with Russell bodies, pseudoepitheliomatous
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hyperplasia of the mucosa, and groups of large vacuolated histiocytes (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.60,61 In 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, histoplasmosis, blastomycosis, paracoccidioidomycosis, and sporotrichosis), and parasites (eg, mucocutaneous leishmaniasis).
Noninfectious processes to be considered include inflammatory conditions, such as Rosai-Dorfman disease and
Wegener granulomatosis, and neoplastic processes, particularly 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.62,63 The disease was described in biblical times, and
the incidence peaked in Europe in the 13th century. The infection 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

A

Leprosy is a spectrum of disease ranging from a localized,
deforming, self-limited process (tuberculoid leprosy [TL]) to
systemic disease that, left untreated, may be fatal (lepromatous
leprosy [LL]).65-67 Between these 2 stages, there are several
borderline forms of the disease (borderline tuberculoid, midborderline, and borderline lepromatous). The disease may
change from one stage to another with treatment. Treatment
often moves the disease process toward TL, whereas decreased
immunosuppression can move borderline or TL toward LL.
Most cases of leprosy are concentrated in Brazil, India,
Madagascar, Mozambique, and Nepal.61,62,66,67 In the United
States, leprosy is rare but is found in parts of Florida,
Louisiana, and Texas, areas of New York City, and Asian and
Mexican communities in California.61,62,66,67
In TL, there is usually a large, ill-defined, numb skin
plaque. The plaque may be seen anywhere on the skin but
often spares the scalp. Spontaneous resolution may take

years, resulting in scars and depigmentation. Progression can
also occur, leading to borderline-type leprosy, and, in rare
cases, untreated patients can develop LL. TL commonly
involves nerves, and patients develop tender, thickened
nerves with loss of sensation and motor function. In LL, there
is often no sensation loss and there is absence of nerve thickening. LL can result in nodules or plaques on the skin. Eye
involvement causes pain, photophobias, decreased visual
acuity, glaucoma, and blindness. Laryngeal involvement
results in stridor and hoarseness. Nasal disease can cause a
saddle-nose deformity, and nasal endoscopy has become a
way in which patients can be followed up.64 LL cannot revert
to less severe forms of the disease.

B

❚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.

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❚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, Lowpower 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.

The diagnosis may require skin or nerve biopsy.
Histologic findings vary according to the type of leprosy.62 In
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 diffuse dermal inflammatory reaction consisting of macrophages,
foamy histiocytes (Virchow, or lepra, cells), and many intracellular 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 leprae–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.68,69 The 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 disease can be limited, but recovery of neuronal function is variable.66,67 Much of the chronic changes result from repeated
trauma to numb extremities. Even when disease is controlled,
the stigma and social isolation often persist.
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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 commonly
involved areas include the pharynx and the conjunctiva.71,72 A
significant 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 following
direct inoculation and can lead to blindness. In neonates, bilateral conjunctivitis often follows vaginal delivery by an infected
mother. Blindness from neonatal gonococcal infection is a serious problem in developing countries but is uncommon in the
United States where prophylaxis during the neonatal period is
common. 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 transfusion.73 T pallidum penetrates abraded skin and intact
mucous membranes and rapidly disseminates through the
lymphoreticular system.

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

D

E

F

spontaneously in 3 to 7 weeks. Secondary syphilis develops
about 4 to 10 weeks after the appearance of the primary
lesion.73 Patients often complain of malaise, fever, myalgias,
and arthralgias. Physical examination may reveal lymphadenopathy 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.74-78 The chancre sore of primary syphilis can involve
oral mucosa.74-78 Patients 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 tertiary syphilis may involve mucous membranes, and in patients
with neurosyphilis, meningitis and dementia may develop.

Oral lesions in primary and secondary syphilis are nonspecific and characterized by squamous hyperplasia and a plasma
cell infiltrate that extends deep into the submucosa.74-78
Although these findings are nonspecific, the presence of a
marked, deeply infiltrating plasma cell infiltrate should alert
pathologists to the possibility of syphilis. Neuritis has also been
described in primary and secondary disease. Mucosal ischemic
changes due to obliterative endarteritis may also be seen.
Tertiary syphilis involving the oral cavity may also show a
chronic inflammatory infiltrate with few plasma cells.74-78
Actinomycosis
Actinomycosis is a subacute to chronic bacterial infection
caused by filamentous, gram-positive, anaerobic to microaerophilic bacteria. The bacteria include Actinomyces israelii,
Actinomyces gerensceriae, Actinomyces naeslundii, Actinomyces
odontolyticus, Actinomyces viscosus, Actinomyces meyeri, and
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Propionibacterium propionicum. Actinomycosis is characterized 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, including the sinuses, mastoid, major salivary glands, and thyroid.85-92
Histologically, infection is characterized by a mixed
suppurative and granulomatous inflammatory reaction.

A

Anthrax
Bacillus anthracis is an aerobic, spore-forming, grampositive bacillus. The organism has received worldwide
attention because of its potential for use as a bioterrorism

B

❚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).

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“Sulfur granules” are for the most part pathognomonic for
infection and can be found in the lesions and in the sinus
drainage ❚Image 7A❚ and ❚Image 7B❚. The granules are
approximately 1 mm in diameter and can be seen by the
naked eye as yellowish particles. Microscopically, the particles are shown to consist of filamentous bacteria surrounded
by neutrophils. Gram stain reveals gram-positive, branching
filaments, 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 controlled
with antibiotics or surgery.

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weapon. There are 3 major forms of infection with the
organism: cutaneous, inhalation, and gastrointestinal.93 The
details of these forms of anthrax will not be discussed with
the exception of gastrointestinal anthrax, which may manifest 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-contaminated food products. Localized ulcers, cervical lymphadenopathy, 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 bacteria93 ❚Image 8❚. The organism can be cultured, and immunostains can be used to identify the organism in smears and
tissue sections.94

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Fungal Diseases
A variety of fungal infections can result in head and neck
manifestations. Head and neck fungal infections have been
associated with mucosal ulceration and erosion, lymphadenopathy, and sinonasal disease. This section will not
detail all types of fungal infections but will concentrate on
sinonasal fungal disease.
Sinonasal Fungal Disease
Sinonasal fungal disease was initially described in the
1600s; however, only recently has this topic become of great
interest. There are 4 types of sinonasal fungal disease: (1)
chronic indolent invasive sinusitis, (2) fulminant fungal sinusitis, (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 invasive
fungal sinusitis.95-99 Chronic granulomatous sinusitis is seen in

B

❚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.

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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 granulomatous reaction to the fungus. Treatment includes surgical
debridement followed by antifungal therapy. Chronic invasive
fungal sinusitis is a slowly progressive, low-grade, invasive fungal infection that usually occurs in patients with diabetes.
Patients have symptoms of long-standing sinusitis and are usually 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 hematologic malignancies and diabetes, although occasionally the
disease may develop in immunocompetent patients.95-99 The
patients get infected with the fungus, and subsequently tissue
and vascular invasion with massive necrosis develop, necessitating 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).95-99 Treatment includes emergency surgery with sinus debridement and intravenous antifungal therapy. Despite therapy, the prognosis is poor.
A fungus ball is a tangled mass of fungus (most commonly A flavus or A fumigatus) in the sinonasal tract (most commonly 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

A

related to a history of trauma or surgery. Histologically, the
specimen consists of a mass of fungal organisms. Little
inflammatory reaction is present ❚Image 10❚. Although the
disease is usually indolent, reports have demonstrated that
these lesions may develop into acute fulminant sinusitis in
previously healthy patients who become immunosuppressed.103
AFS occurs in immunocompetent patients with nasal
polyps, atopy, and asthma in whom an allergic immune
response 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.112-114 AFS represents approximately 10%
of all chronic sinusitis cases requiring surgery. Studies have indicated that AFS may be more common than previously thought.
A group from the Mayo Clinic grew fungal organisms in washing specimens from 96% of patients with chronic sinusitis.115
However, this study has been criticized because the patients may
not have fulfilled the diagnostic criteria for AFS.116
AFS can be seen in patients of any age or sex, and the diagnosis is suspected based on clinical manifestations and characteristic computed tomography scan or magnetic resonance imaging findings.95-99,104-111,117 Patients may have facial deformities
and visual loss. The diagnosis is confirmed by histologic examination 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 understood, AFS is considered to represent a hypersensitivity reaction

B

❚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).

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to fungal organisms that have colonized the sinonasal tract but
have not invaded surrounding tissues.118,119 Predisposing factors 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 reproduce 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 promoting 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, dilated, 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 fungal cause even without histopathologic identification of fungus.
Allergic mucin has been described in patients without evidence

A

of fungal infection. This has been termed eosinophilic mucinous rhinosinusitis and suggests that allergic mucin may be a
response to another allergen.120-122
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 patients
with nasal polyps, atopy, and refractory chronic sinusitis and
is suggested by characteristic computed tomography scan
findings, including rounded soft tissue masses, polypoid nasal
mucosal thickening, bony remodeling, and/or expansion of the
nasal cavity or paranasal sinuses.105,106,110,116,118 Because
some patients may show only local mucosal allergy, the diagnosis of allergic disease should be thoroughly sought in
patients who have a clinical history suggesting allergic disease
despite 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 to
restore normal sinus drainage and ventilation. Medical therapy includes nasal steroids and, sometimes, oral steroid therapy, especially for patients with recurrent, aggressive AFS and
severe atopy. Antifungal therapy is not used.

Viral Infections and Virally Related
Diseases
A variety of viral and virally related diseases show head
and neck manifestations. Viruses are associated not only with

B

❚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).

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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 adenovirus. Paramyxovirus (mumps virus) infects the parotid
and submandibular gland, resulting in salivary gland
enlargement. Detailed pathologic changes of these infections will not be discussed.
Molluscum Contagiosum
Molluscum contagiosum is a DNA poxvirus that can produce cutaneous infection almost anywhere, including the head
and neck area, particularly the face.124,125 The infection results in
umbilicated papules on the skin and is spread by close contact.
The disease is self-limited in immunocompetent patients; however, 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 dermatitis.124,125 Oral infection is commonly seen in immunocompromised 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 pathognomonic 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

A

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 the
histopathologic findings are so classic.129 As mentioned, the
disease is usually self-limited, but untreated ocular involvement can lead to scarring and pain in infected children.
HIV
Infection with HIV (an RNA Lentivirus) can manifest in
several ways in the head and neck area. Many of these
lesions have been (or will be) discussed separately. Almost
70% of HIV-infected patients will have lesions involving the
head and neck.130-136 Sinusitis, mucosal ulceration, candidiasis, Kaposi sarcoma (KS), salivary gland enlargement, lymphadenopathy, chronic sinusitis, and many other entities may
be seen. It is believed that the incidence of head and neck
lesions associated with HIV has been decreasing with antiviral therapy.131,132
Oral Mucosal and Sinonasal Lesions
Mucosal ulcerations are commonly identified in HIV+
patients.130,132,133,136 These ulcerations may be due to infections with viruses, bacteria, or fungus. In addition, painful,
aphthous ulcers of unknown cause may occur on the mucosal surfaces of the oropharynx ❚Image 13❚. Another form of
ulceration is that associated with neutropenia. This type of
ulcer is seen in patients with neutrophil counts less than
800/àL (0.8 ì 109/L). Like the aphthous ulcers, the cause is
unknown. HIV+ patients have an increased incidence of dental caries, which is believed to be from xerostomia due to

B

❚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.

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B

❚Image 12❚ Molluscum contagiosum. A, A facial skin lesion in an HIV+ male showing the characteristic viral inclusions of molluscum
contagiosum (H&E, ×25). B, Higher power view of the characteristic viral inclusions of molluscum contagiosum (H&E, ×100).

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 sinusitis 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 nonHIV+ patients and often does not respond to antibiotic therapy. In later stages, the infectious agents are more likely to be

viruses, fungi, and, rarely, bacteria such as Pseudomonas
aeruginosa.134 Neoplasms 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 expansion with increased immunoblasts, plasma cells, and vascular proliferation and multinucleated giant cells, especially
early in the infection.137-139 Other causes of lymphadenopathy 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.133 Usually 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 intraparotid lymph nodes, malignant lymphoma, or the development of benign lymphoepithelial cysts. The benign lymphoepithelial cysts are often multiloculated and most likely result

❚Image 13❚ Oral ulcers in HIV. Gross appearance of aphthous
ulcers in an HIV+ person. The cause of these ulcers is often
unknown. Photograph courtesy of Centers for Disease
Control and Prevention/Sol Silverman, Jr, DDS, via the Public

Health Image Library.

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patients are at risk for disseminated disease. Following primary infection, the virus may become latent in neural tissues,
particularly dorsal root ganglion, spinal cord, sympathetic
ganglion, and peripheral nerves.
Acute Herpetic Gingivostomatitis
Acute herpetic gingivostomatitis is the most common manifestation of primary HSV-1 infection in young children.145-149
The virus is transmitted by saliva from an infected adult or child,
and the incubation period is from days to weeks. Clinically, the
child has high fever, irritability, and inability to eat or drink.
Findings include severe gingivitis and vesicular lesions on the
tongue, buccal mucosa, and palate with extension to the lips and
face. Reactive cervical adenopathy may be evident. The disease
lasts between 3 days and 3 weeks, and patients may still remain
infectious for days to weeks after symptoms have disappeared.
❚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.

from metaplastic and cystic changes within reactive lymph
nodes131-135,140-142 ❚Image 14❚. When first described, the management of these cysts was considered to be surgical excision,
but owing to their benign nature, more conservative management 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, psoriasis, viral infections, pruritic papular eruptions, eosinophilic
folliculitis, and cutaneous carcinomas (squamous cell carcinoma and basal cell carcinoma).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
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Acute Herpetic Pharyngotonsillitis
Acute herpetic pharyngotonsillitis is usually seen in adolescents and adults infected with HSV-1 for the first time.
Instead of gingivostomatitis as seen in children, patients have
pharyngotonsillitis.145,147,148 Clinically, patients have fever,
malaise, odynophagia, and headache. Vesiculoulcerative lesions
develop on the tonsils. Primary HSV-2 infection may show similar findings following infection by orogenital contact.
Recurrent Orolabial Herpetic Infection (Herpes Labialis)
Once HSV infection has occurred, the virus often enters
a latent state. Reactivation of the viral infection, especially
HSV-1, results in herpes labialis. Reactivation may be associated with other illnesses, trauma, or even sun exposure.
Patients have vesicles involving the mouth and lips. There is
often a prodrome of pain, tingling, burning, or itching.
Ocular HSV Infection
HSV can also cause keratoconjunctivitis. Patients have
acute pain, tearing, itching, and swelling. Rarely, retinal
necrosis can develop, which can lead to blindness.150,151
HSV Diagnosis
The diagnosis of HSV infection can be made by the clinical manifestations in many cases. If necessary, a Tzanck
smear 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, although
other cell types can be infected. The infected cells may undergo amitotic division, resulting in the formation of multinucleated giant cells. The nuclei of HSV-infected cells demonstrate
eosinophilic intranuclear inclusions (Cowdry type A) and
marginated nuclear chromatin (“ground-glass” nuclei)
❚Image 15❚. Treatment is usually with acyclovir, which can be
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A

B

❚Image 15❚ Herpes simplex virus (HSV). A, Section of a larynx in an immunosuppressed elderly man with disseminated HSV-1
infection diagnosed at autopsy. The squamous epithelium shows characteristic ground-glass nuclear inclusions (H&E, ×25). B,
Higher power view of laryngeal HSV showing ground-glass nuclear and Cowdry type A inclusions (H&E, ×100).

used to treat the outbreak and for prophylaxis to avoid repeated bouts of disease.
Cytomegalovirus
CMV infection may result in head and neck manifestations, including extensive mucosal ulceration, especially in the
oropharynx and the sinonasal tract.152-154 Patients have sore
throat, odynophagia, and dysphagia. Oftentimes, the symptoms

A

overlap with those seen in infectious mononucleosis. Clinically
significant infections are seen more frequently in immunosuppressed patients. Retinitis is also a known result of CMV infection155-157 ❚Image 16A❚. Other head and neck sites that may be
involved by CMV include the parotid, larynx, and thyroid158-160
❚Image 16B❚.
The diagnosis of CMV includes tests for serum CMV antigens, qualitative and quantitative PCR assays on blood and tissue

B

❚Image 16❚ Cytomegalovirus (CMV). A, Retinal tissue in an immunosuppressed female with lymphoma with confirmed CMV
retinitis (H&E, ×25). There is diffuse retinal necrosis. B, Classic cytomegalic inclusions of CMV in the parotid of an
immunosuppressed patient (H&E, ×50). Photographs courtesy of Centers for Disease Control and Prevention/Dr Feldman (A)
and Dr Haraszti (B), via the Public Health Image Library.

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samples, and shell vial assays. The hallmark of CMV infection
is the finding of intranuclear inclusions consistent with herpesvirus infection. The cells are often significantly enlarged and
show nuclear and cytoplasmic inclusions. CMV infection may
be confirmed by using in situ hybridization or immunohistochemical 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 initial 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, reactivation may lead to Ramsay Hunt syndrome, which is characterized by peripheral facial palsy, pain in the ear and face, and

A

B

❚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).

C

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vesicles in the external ear canal.161,162 Reactivation of virus
involving the ophthalmic division of the trigeminal nerve can
results in herpes ophthalmicus.161,162 Patients will have conjunctivitis or corneal ulcers, and complications include blindness. In some cases of herpes ophthalmicus, the virus will
migrate along the intracranial branches of the trigeminal nerve,
causing vascular thrombosis resulting in paralysis.161,162
The Tzanck preparation can be used to identify viral
inclusions as in HSV infection. Cytologic and histologic
examination of the VZV vesicles will not differentiate VZV
from HSV infection ❚Image 17❚. Intranuclear eosinophilic
inclusions and ground-glass nuclear changes are seen in
epithelial cells in both infections. Leukocytoclastic vasculitis
and hemorrhage are more common in VZV lesions than in
herpes simplex. Immunohistochemical, in situ hybridization,
and PCR techniques on tissue samples can be used to differentiate VZV from HSV.

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Treatment for VZV infection depends on the patient’s
symptoms, age, and immune status. Early intervention (at the
onset of skin rash) with antiviral therapy can decrease the
duration of symptoms and may possibly decrease the chance
of postherpetic neuralgia.161,162
Epstein-Barr Virus
Infectious Mononucleosis.—EBV has been implicated in
several disease processes. The majority of adults have serologic
evidence of exposure to the virus. Infections are often asymptomatic in young children. In adolescents and young adults, infection often results in the development of infectious mononucleosis.163,164 In infectious mononucleosis, EBV infects B cells
resulting in B-cell activation and proliferation. The host T cells
and natural killer (NK) cells respond to the infection to destroy
the proliferating B cells. Patients with infectious mononucleosis
often have high fever, sore throat, and lymphadenopathy.
Marked tonsillar enlargement may require intubation.165
Laboratory findings include atypical lymphocytosis and the
presence of heterophil antibodies.165 Monospot tests and EBV
serologic tests are often useful in establishing the diagnosis.
Lymph node biopsy is not usually warranted; however, if it is
performed, one may see expanded cortical areas containing a
mixture of mitotically active lymphoid cells, including small
and large lymphocytes, immunoblasts, tingible body
macrophages, and rare plasma cells.166 Cytologic atypia, ReedSternberg cells, and necrosis may be apparent. Care must be

taken to avoid overinterpretation of the changes as malignant.
The illness is self-limited, and treatment is supportive; however, infection may be disseminated and fatal and may also
result in secondary bacterial and fungal infections that are life

A

threatening165,167,168 ❚Image 18❚. Antiviral medications are usually not effective. Following primary infection, the virus
becomes latent in hematolymphoid organs.
Oral Hairy Leukoplakia.—Oral hairy leukoplakia (OHL) is
caused by infection of oral squamous epithelial cells with EBV
and is most commonly seen in patients with HIV infection but
may be seen in other immunosuppressed patients and in patients
who are otherwise healthy.130-136,169-173 The entity is characterized
by productive EBV infection.174 The lesions are white and shaggy and occur most commonly on the lateral border of the tongue
❚Image 19A❚, although lesions may also involve the dorsal or ventral surface of the tongue, buccal mucosa, and gingiva.130-136,169-173
The lesions are nonpainful and frequently change in appearance.
HIV+ patients who are smokers and have decreasing CD4 counts
are at increased risk for development of OHL.169 In addition,
increased HIV viral load, the presence of oral candidiasis, previous use of fluconazole, and systemic acyclovir have been associated with OHL.169 Treatment of HIV with antiretroviral medication is believed to have reduced the incidence of OHL.130,131 The
differential diagnosis includes Candida infection (thrush), irritation due to other factors, neoplasia, human papillomavirus infection, tobacco-associated leukoplakia, lichenoid inflammatory
eruptions, and syphilis.130-136,173,175
The diagnosis is usually made clinically. Biopsy is
sometimes performed to rule out other causes of leukoplakia,
especially squamous dysplasias or malignancies.
Histologically, the lesions are characterized by hyperkeratosis
or parakeratosis, acanthosis of the stratum spinosum with cells
that show nuclear clearing (ground glass), and, sometimes,
Cowdry type A inclusions173,175 ❚Image 19B❚. There is minimal
surrounding inflammatory response, and the basal layer

B

❚Image 18❚ Infectious mononucleosis. A, Classic atypical perivascular lymphocytic infiltrate observed in a cervical lymph node in
a 17-year-old girl with disseminated infectious mononucleosis (H&E, ×50). B, This patient died of secondary infection with
Aspergillus (H&E, ×50). Secondary infection is often a cause of death in patients with disseminated infectious mononucleosis.

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appears normal. The lesions often can become superficially
infected with Candida organisms. The diagnosis requires not
only the characteristic histologic findings but also the presence of lytic EBV nucleic acids or proteins in the infected
cells.173-175 Diagnosis can also be made by using cytologic
preparations that look for characteristic squamous cells with
clear nuclei and marginating cytoplasm classic of lytic viral
infections ❚Image 19C❚. Treatment includes antiviral therapy
and topical treatment with podophyllin or retinoic acids.
EBV-Induced Posttransplantation Lymphoproliferative
Disorder (PTLD).—PTLD is a serious complication of organ
transplantation that is seen in 1% to 10% of all allograft recipients depending on the transplanted organ and the types and

dosage of immunosuppression medications used.176-182 These
lymphoproliferations show a spectrum of clinical and histologic findings ranging from reactive B-cell hyperplasia to
large cell lymphoma and may manifest from within 1 month

A

B

❚Image 19❚ Oral hairy leukoplakia (OHL). A, Classic gross
appearance of the tongue in OHL in a male patient with AIDS.
B, Histologically, there is parakeratosis and ballooning of the
superficial layers of the squamous mucosa (H&E, ×50). OHL is
caused by actively replicating Epstein-Barr virus infection in the
oral mucosa. The infection almost never clears. C, Cytologic
preparation of a smear from a tongue lesion in an HIV+ male.
There is nuclear clearing with margination of the chromatin
(H&E, ×250). This finding is consistent with the diagnosis of
OHL. Photographs courtesy of Centers for Disease Control and
Prevention (CDC)/J.S. Greenspan, BDS, University of California,
San Francisco, and Sol Silverman, Jr, DDS (A), via the Public
Health Image Library; CDC/Sol Silverman, Jr, DDS (B), via the
Public Health Image Library; and Faizan Alawi, MD, Oral
Pathology, University of Pennsylvania Medical Center,
Philadelphia (C).

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to several years after engraftment. Disease can be localized or
systemic and is often associated with EBV infection. PTLD
needs to be recognized clinically and histopathologically
because the lymphoproliferations may regress following
reduction of immunosuppression; however, a substantial proportion may progress to disseminated lymphoma.183
The majority of PTLDs result from EBV-induced Bcell expansions. Infection of B cells with EBV results in the
synthesis of several EBV nuclear antigens that can induce
expression of B-cell activation markers, resulting in B-cell
proliferation. In a healthy host, cytotoxic T cells recognize and
destroy the infected B cells. In immunosuppressed transplant
recipients, EBV-infected B cells can proliferate without control. Early on, these proliferations may regress spontaneously
or, if clinically recognized, by reducing immunosuppression.
The clinical manifestations of PTLD are variable. Some
patients are asymptomatic and have a localized mass lesion,

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whereas others show systemic symptoms including fever,
pharyngitis, and multisystem organ failure, findings similar to
those seen in severe acute infectious mononucleosis. In the
head and neck area, PTLD can manifest almost anywhere and
has been described in lymph nodes, tonsils, adenoids, oropharynx, thyroid, parathyroid, hard palate, parotid gland, nasopharynx, trachea, submandibular gland, lacrimal gland, and conjunctiva.179 Head and neck involvement has been reported as a
cause of sudden respiratory compromise in children.184,185
Histopathologically, PTLDs can be classified in a variety of ways. Nalesnik et al179 proposed classification based

on the morphologic features of the infiltrate as polymorphous or monomorphous PTLD. Polymorphous PTLD contains an infiltrate composed of a variety of cell types, including small and large lymphocytes, plasma cells,
immunoblasts, and transformed lymphocytes ❚Image 20❚.
These lesions, while polymorphous, can be polyclonal,
oligoclonal, or monoclonal by immunohistochemical analysis or by analysis for immunoglobulin heavy or light chain
gene rearrangements. Monomorphous lesions are almost
consistently monoclonal. Patient outcome based on this
pathologic classification is difficult to predict. Some monoclonal lesions regress, whereas others progress to disseminated disease and death in a short time.
A newer classification scheme was reported by Harris et
al.186 This system includes 3 main categories: (1) early
lesions: a proliferation of plasma cells and plasmacytic-type
cells with minimal atypia; tendency to show scattered EBV+
cells by in situ hybridization; lesion often regresses with or

A

even without immunosuppression reduction, often polyclonal,
no genetic abnormalities, and often not fatal; (2) polymorphous PTLD: a proliferation of lymphoid cells consisting of a
mixture of small and large lymphocytes, plasma cells, and
immunoblasts with cytologic atypia; individual cell and zonal
necrosis often seen; frequent diffuse positivity for EBV by in
situ hybridization; lesions show a spectrum from reactive lymphoid hyperplasia to polymorphous B-cell lymphoma, often
monoclonal by gene rearrangement studies, not associated
with genetic abnormalities, and almost always regresses; (3)
monomorphous PTLD: a proliferation of atypical lymphoid
cells of a single cell type, usually immunoblasts or plasmablasts, and histologically resemble immunoblastic lymphoma or plasmablastic myeloma; lesions clonal, possibly
associated with genetic alterations (c-myc and p53 mutations),
and have uniformly fatal outcome.
EBV can be detected in patients with PTLD by several
methods.187-190 Serologic examination may reveal recent EBV
infection or reactivation of past EBV infection. Southern blot

analysis using DNA probes specific for the EBV long terminal
repeats can determine if the lymphoid proliferation is secondary to a clonal expansion of EBV-infected cells. Rapid, accurate in situ localization techniques for EBV DNA, RNA, and
proteins are easily performed in many pathology laboratories.
The treatment for PTLD is variable. Most lymphoproliferations regress with reduction of immunosuppression or with
no treatment. Some studies have tried treatment with anti–B
cell antibodies or with donor mononuclear cell infusions with
mixed results.190,191 Studies have shown that reconstitution of

B

❚Image 20❚ Posttransplantation lymphoproliferative disorder (PTLD). A, A tonsillar mass in a young male after kidney and
pancreas transplantation. Note the polymorphous atypical lymphoid infiltrate (periodic acid–Schiff, ×100). This lesion was clonal
by immunoglobulin heavy chain gene rearrangements. Following reduction of immunosuppression medications, the PTLD
resolved. B, In situ hybridization for Epstein-Barr virus small RNA is positive in many of the atypical lymphocytes
(diaminobenzidine/hematoxylin counterstain, ×100).

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EBV-specific T-cell immunity using EBV-specific autologous

cytotoxic T cells obtained before transplantation and infused
after transplantation remained cytotoxic against EBV and may
be able to reduce the incidence of PTLD.192
X-Linked Lymphoproliferative Disease (Duncan
Disease).—X-linked lymphoproliferative disease is a disease
caused by an inherited immunodeficiency state in which
patients (mainly males) develop infectious mononucleosis,
acquired hypogammaglobulinemia, or malignant lymphoma
following EBV infection.164,180-182,193-197 Patients have a
defect in the ability to regulate EBV infections; however,
response to other infectious agents does not seem to be
impaired. The pathology is similar to that seen in EBV-associated PTLD and fatal infectious mononucleosis.164,180-182
About two thirds of patients die of fatal infectious mononucleosis. An additional 20% will develop lymphoma if they survive the initial EBV infection. About 85% of patients will die
in childhood. There is 100% mortality by 40 years of age.
Burkitt Lymphoma.—Burkitt lymphoma, a high-grade Bcell lymphoma, is another EBV-associated malignancy. There
are 2 forms of the disease, the endemic (African) form and the
nonendemic (sporadic) form.198 The endemic form is associated with a combination of EBV infection and malaria. Recent
studies have also implicated a third agent, mosquito-transmitted
arbovirus, and arbovirally related illnesses have been
described in patients before the onset of the lymphoma.199 The
nonendemic form is often not EBV-related unless it is seen in
immunosuppressed patients. Burkitt lymphoma is one of the
fastest growing malignancies. The endemic form most commonly infects the jaw (maxilla or mandible) of children.198
Histologically, Burkitt lymphoma is characterized by a
proliferation of small noncleaved B cells that are uniform in
appearance and show a “starry sky” appearance, which is secondary to the presence of scattered tingible body macrophages
due to the tumor’s high proliferative rate.200 In situ hybridization for EBV small encoded RNA, a marker of latent EBV
infection, often highlights many cells in the endemic Burkitt
lesions. A study showed evidence of lytic EBV infection in the
cells adjacent to the tingible body macrophages that induce

the starry sky appearance.201
Most Burkitt lymphomas carry a t(8;14) that results in a
fusion of the c-myc gene on chromosome 8 with the
immunoglobulin heavy chain gene on chromosome 14. Other
gene rearrangements include t(8;2) (fusion with κ light chain
gene) and t(8;22) (fusion with λ light chain gene).198
Although Burkitt lymphoma is considered a small cell lymphoma, it is often difficult to distinguish Burkitt lymphoma
from diffuse large B-cell lymphoma based on pure histologic
features. This distinction is important because the treatment
protocols are different. Recent studies have used gene expression profiling to aid in this distinction. Burkitt lymphoma
specimens are more likely to have high expression of c-myc
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target genes and germinal center B-cell genes compared with
large cell lymphomas.202,203
Sinonasal NK/T-Cell Lymphoma.—Sinonasal NK/T-cell
lymphomas (angiocentric lymphoma/CD56 lymphoma) are a
group of high-grade, aggressive lymphomas that have a
propensity to occur in the nose and paranasal sinuses.204,205
Other names for this tumor include lethal midline granuloma,
polymorphic reticulosis, and midline malignant reticulosis,
although the preferred terminology is sinonasal NK/T-cell
lymphoma.204,205 The tumors are more commonly seen in men
older than 40 years. They peak during the fifth decade. These
tumors are uncommon in the United States, constituting fewer
than 1% of lymphomas, but are common in Asia and Central

and South America.204,205
Histologically, these tumors are composed of large
atypical lymphocytes with enlarged, hyperchromatic, and
convoluted nuclei admixed with smaller lymphocytes, plasma cells, and histiocytes. The tumor cells often infiltrate
large blood vessels, resulting in zones of tissue necrosis;
however, this feature is evident in only 70% of tumors204
❚Image 21A❚ and ❚Image 21B❚. Immunophenotypically, the
lesional cells are positive for CD56, a marker of NK cell
differentiation, CD2, CD7, and CD8 and are negative for
CD3 and CD5.204,205 The tumors often express T-cell intracellular antigen-1 (TIA-1), perforin, and FAS (CD95/Apo1) ligand.206 T-cell receptor gene rearrangement studies are
negative.204,205 The Epstein-Barr viral genome is almost
always identified in lesional cells, indicating a primary role
for this virus in disease pathogenesis207 ❚Image 21C❚.
Mutations of p53 and c-kit have been described.208 In addition, alterations in chromosomes 1, 2, 12, 10, 13, and 17
have been reported.209
Localized disease may be treated with radiation, with the
majority of patients showing a complete remission.
Disseminated disease may involve the skin, regional lymph
nodes, lungs, and brain. The prognosis for disseminated disease is poor. Recent studies have found that adoptive transfer
of EBV-specific cytotoxic T cells may be useful in treating
patients with disseminated disease.210
Nasopharyngeal Carcinoma.—Nasopharyngeal carcinomas are another EBV-associated malignancy. The World Health
Organization (WHO) has classified nasopharyngeal carcinoma
into 3 categories: WHO-1, keratinizing squamous cell carcinoma; WHO-2, nonkeratinizing squamous cell carcinoma; and
WHO-3, undifferentiated carcinoma. This latter entity is almost
always EBV-associated.198,211,212 Nasopharyngeal carcinoma
has a bimodal age distribution. A small peak is observed in late
childhood, and a second peak occurs in people 50 to 60 years
old. People of Asian and North African descent are also more
commonly affected. In the United States, WHO-3 nasopharyngeal carcinoma is more commonly seen in black teenagers.211,212

The pathogenesis of the tumor is largely unknown, but EBV
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A

C

infection coupled with overexpression of p53 and loss of p16
and p27 protein expression has been suggested.213
Nasopharyngeal carcinoma rarely comes to medical
attention before it has spread to regional lymph nodes, and, in
fact, diagnosis is often made initially on cervical lymph node
biopsy. Enlargement and extension of the tumor can result in
nasal obstruction, bleeding, hearing loss, and cranial nerve
palsies. Endoscopic examination reveals a mass arising in the
nasopharynx, most frequently in the fossa of Rosenmüller. A
paraneoplastic osteoarthropathy has been described in patients
with widespread disease.214 Most cases of WHO-3 disease
contain EBV nucleic acids within the malignant epithelial
cells. In fact, the presence of EBV-infected cells in a carcinoma metastatic to cervical lymph nodes is highly suggestive of
a nasopharyngeal primary site.215 EBV expression has been
shown to be an independent prognostic factor associated with
better prognosis in some studies.216

B

❚Image 21❚ Nasal T-cell/natural killer (NK)-cell lymphoma. A,

Nasal NK-cell lymphoma showing a markedly atypical lymphoid
reaction surrounded by zones of necrosis (H&E, ×25). B,
Higher power view showing the lymphoid atypia of sinonasal
NK-cell lymphoma (H&E, ×100). C, In situ hybridization for
Epstein-Barr virus small RNA is positive in the lymphoma cells
(diaminobenzidine/hematoxylin counterstain, ×100).

Histologically, WHO-3 lesions are characterized by the
presence of large atypical nucleolated epithelial cells that
grow singly or in a nested pattern and are often surrounded by
a lymphoplasmacytic infiltrate ❚Image 22❚. Recent studies
have identified in situ nasopharyngeal carcinoma that seems to
precede an invasive diagnosis by about 4 to 5 years. EBV
nucleic acids are identified in these noninvasive lesions.217,218
With a diagnosis of nasopharyngeal carcinoma, EBV
titers, including IgA and IgG antibodies to the viral capsid
antigen, should be performed. These titers correlate with
tumor burden and decrease with treatment. They are an excellent means for monitoring response of the neoplastic process
to therapy and for detection of tumor recurrence.219
Human Herpesvirus 6
HHV-6 is a virus that most commonly infects the
oropharynx in early childhood. Disease is characterized
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A

B

❚Image 22❚ Nasopharyngeal carcinoma. A, Undifferentiated nasopharyngeal carcinoma in a 55-year-old man (H&E, ×50). B, In
situ hybridization for Epstein-Barr virus small RNA is positive in the carcinoma cells. The lymphocytes are negative
(diaminobenzidine/hematoxylin counterstain, ×25).

by a fever and rash (roseola).147,220-223 Latent virus seems
to be in salivary gland and lymphoid tissues.224 Adults
infected with HHV-6 may have a mononucleosis-like illness.221-223 The virus has been implicated in some cases
of Hodgkin disease and angioimmunoblastic lymphadenopathy.220-223
Human Herpesvirus 7
Infection with HHV-7 usually occurs during childhood.147,221-223 The most common manifestation of the infection is fever. The virus has been identified in pharyngeal tissues
in adults.224 There are no known associations with systemic
disease processes.
Human Herpesvirus 8 (KS Herpesvirus)
HHV-8 is a γ herpesvirus that has been associated with a
variety of neoplastic states, including KS, the plasma cell
variant of Castleman disease, and effusion-based lymphomas.225-227 Primary infection with the virus is usually
characterized by a maculopapular rash and long-standing
fever. Like other herpesviruses, the virus becomes latent following primary infection. Recent studies have suggested lymph
node as the site of latency.224 Reactivation of the virus can
lead to the development of the aforementioned malignancies,
the most common of which is KS. Almost all cases of KS

contain the HHV-8 genome.
KS frequently occurs with head and neck manifestations,
including involvement of skin, mucosal surfaces, and lymph
nodes. There are 4 variants of KS143,228: (1) classic, usually seen
on the lower extremities of older men; (2) endemic, which usually occurs in Africa and involves skin and lymph nodes; (3)
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transplant-related, in which the tumor is seen in solid organ recipients; and (4) AIDS-related, seen in patients with AIDS and highly aggressive and often disseminated. Before treatment with
antiviral therapy for HIV, many patients with AIDS died of KS.
KS manifests clinically and pathologically in a variety of
ways143,228 ❚Image 23❚: The patch stage is characterized by the
presence of a flat lesion that shows a proliferation of numerous vascular spaces within the dermis. The slit-like vessels are
present around preexisting blood vessels, skin adnexa, and
dermal collagen bundles. The neoplastic vessels are lined by
plump, atypical endothelial cells. Glomerular-like vascular
proliferations may be evident. Extravasated RBCs and hemosiderin may be present. The differential diagnosis includes
granulation tissue.
The plaque stage shows more prominent spindle cells that
blend together with the slit-like vascular spaces. The proliferation involves the superficial and deep dermis and subcutaneous tissue. There are often hemosiderin deposition and
PAS-positive hyaline globules.
The nodular stage shows a defined lesion characterized
by prominent spindle cells surrounding slit-like vascular
spaces. RBC extravasation is prominent. The features are
more prominent than those in the plaque stage. PAS-positive
hyaline globules are evident.
Other appearances include lymphadenopathic, exophytic,

infiltrative, ecchymotic, telangiectatic, keloidal, and cavernous-like.228
The first line of treatment in AIDS-related KS is the
control of HIV replication. With improvement of antiretroviral therapy, the incidence of AIDS-related KS has declined
significantly.229
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A

B

C

D

E

❚Image 23❚ Human herpesvirus 8 (Kaposi sarcoma [KS] virus).
A, Gross appearance of a KS lesion on the gingiva of an HIV+
male. Photograph courtesy of Centers for Disease Control and
Prevention (CDC)/Sol Silverman, Jr, DDS, via the Public Health
Image Library. B and C, Skin biopsy specimen in an HIV+ male
showing a dermal vascular proliferation invading among the
dermal collagen bundle fibers consistent with KS (B, H&E,
×25; C, H&E, ×50). D, Numerous hyaline globules in KS (H&E,
×100). Photograph courtesy of CDC/Edwin P Ewing, MD, via
.
the Public Health Image Library. E, Immunohistochemical stain

for human herpesvirus 8 in KS showing nuclear staining in the
vascular endothelial cells (diaminobenzidine/hematoxylin
counterstain, ×50).

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Human Papillomavirus Infection
Human papillomavirus has been implicated in a variety of
papillomatous and malignant squamous proliferations, including those seen in the head and neck area such as sinonasal
papillomas, laryngeal papillomas, and squamous cell carcinoma.230-234 The details of these lesions will not be discussed.

Protozoal Diseases
Rhinosporidiosis
Rhinosporidiosis is a chronic infection of the mucous
membranes that typically involves the nose, nasopharynx,
conjunctiva, and lacrimal ducts.235,236 The disease is caused by
Rhinosporidium seeberi and usually manifests grossly as friable, hemorrhagic polyps.237 The infection is endemic to
India, Sri Lanka, South America, and Africa, with the overwhelming majority of cases originating in India and Sri
Lanka.235 The disease is rare in the United States, but infection

has been reported in Texas and the Southeast.235
R seeberi has not been grown in culture, but with rRNA
analysis, the organism has been established as a protistan parasite in the class Mesomycetozoea, which contains organisms
that produce similar diseases in fish and amphibians.238,239
Rhinosporidiosis is typically limited to the mucosal epithelium. Infection usually results from traumatic inoculation of the
organism. The organism locally replicates, and the immune
response to the organism induces hyperplastic growth of the
infected tissue.

❚Image 24❚ Rhinosporidiosis. Nasal polyp lesion
demonstrating submucosal organisms consistent with
Rhinosporidium seeberi (H&E, ×50). Photograph courtesy of
Centers for Disease Control and Prevention/Martin Hicklin,
MD, via the Public Health Image Library.

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Most patients have unilateral nasal obstruction or bleeding. Gross examination reveals soft, friable “strawberry-like”
polyps in the infected sites.237 Histologically, the sporangia of
R seeberi are observed beneath the normal epithelium ❚Image
24❚. They are associated with inflammatory cells, including
neutrophils, lymphocytes, plasma cells, multinucleated giant
cells, and scattered granulomas. The overlying epithelium is
hyperplastic and shows hypervascularity. At times, rhinosporidiosis may be confused with the changes seen in
cylindrical cell papilloma (oncocytic schneiderian papilloma); however, the cysts seen in cylindrical cell papillomas are
intramucosal, not submucosal as in rhinosporidiosis. Diagnosis

can also be made by FNA cytology of mass lesions.240 Treatment
involves surgical excision of the lesions. The prognosis is
excellent, except in patients with disseminated disease.241,242
Leishmaniasis
Leishmaniasis is a disease caused by the protozoa
Leishmania, transmitted by the female sandfly. There are
many species, and the spectrum of disease is broad.243-245
There are 3 forms of disease: (1) cutaneous, which is most
common; (2) visceral; and (3) mucocutaneous, which is the
rarest form. In addition, infection may be subclinical. In the
United States, the disease is uncommon but is endemic in
parts of southwest Texas.246 Most other cases in the United
States are identified in immigrants from countries where the
infection is endemic. Infection in soldiers returning from the
Middle East is being increasingly seen.247,248 More than 1 million cases of cutaneous leishmaniasis are diagnosed annually
in countries where sandflies are common, including
Afghanistan, Brazil, Iran, Iraq, Peru, and Saudi Arabia.249
Visceral leishmaniasis is most common in Bangladesh, Brazil,
India, Nepal, and Sudan.249
The organism’s life cycle begins in the gut of the sandfly,
but the organism completes its life cycle in the host following
the fly bite. The sandfly inoculates the host with the organisms
in the promastigote stage. Once the organisms are inoculated,
they are phagocytized by host macrophages. The promastigotes
then replicate as amastigotes and infect additional macrophages
locally or, if the organisms have disseminated, systemically.
Cutaneous leishmaniasis is characterized by the presence
of skin lesions on exposed areas, similar to leprosy. The initial
lesions are seen several weeks after inoculation. Some cases
of cutaneous disease may spontaneously resolve, or the disease can become debilitating, resulting in significant scarring

and disfigurement.
Visceral leishmaniasis incubates for weeks to months
before clinical manifestation. The disease onset can be acute,
subacute, or chronic. It can be indolent and self-limited, but
may also be disseminated and fulminant. Symptoms of visceral leishmaniasis include weight loss, fever, leukopenia,
hepatosplenomegaly, diarrhea, and lymphadenopathy.249,250
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The least common form of leishmaniasis is mucocutaneous. The ulcerated mucosal lesions seen in this form of the
disease are due to the disseminated spread of the organism from
the initial site of infection. The ulcers often become secondarily infected with bacteria. The mucosal lesions can involve the
oral mucosa, pharynx, lacrimal glands, nasal mucosa, larynx,
and other sites.251-255 If untreated, there may be erosion of the
nasal septum and the palate, resulting in facial disfigurement.
Cytologic evaluation of nasal smears can be used to evaluate
treatment efficacy in patients with nasal involvement.256
In endemic countries where tests are not usually available,
the diagnosis is made on a clinical basis. If tissue specimens
are obtained, the organism may be seen by H&E staining, especially in cases of cutaneous and visceral leishmaniasis. Skin
tests may reveal positive results months after the initial lesions
are observed. Special immunohistochemical assays and
molecular genetic testing can be used to identify the species of
the organism. In cutaneous leishmaniasis, serum anti–leishmanial antibody can be detected; however, diagnosis is usually
made by identification of the organisms in tissue or cytologic
specimens.249 Material from the ulcer base usually has the
highest yield. Detection of the organism’s nucleic acids in
lesional material by PCR is usually the most sensitive method

for the diagnosis of cutaneous and mucocutaneous disease.
For visceral leishmaniasis, diagnosis is best made by direct
visualization of organisms in clinical specimens.249 Serum
anti–leishmanial IgG in high titer can also be diagnostic. Tests
for leishmanial antigen or antibody in the urine are newer
techniques used for diagnosis of visceral disease.249
Immunohistochemical analysis and in situ hybridization have
been used to identify the organisms in tissue samples.257

A

Microscopically, the parasites appear as 1.5- to 3-µm
ovoid to round organisms within histiocytes ❚Image 25❚. In
human tissue, Leishmania organisms appear as amastigotes.
The organisms are identified on H&E and Giemsa stains on
smears. In tissue sections, Giemsa stains are not usually useful, but the organisms may be highlighted with Brown-Hopps
modified Gram stain. Differential diagnosis includes small
fungi such as Histoplasma and Penicillium.
The complications of leishmaniasis include secondary bacterial infection of ulcerated lesions, bleeding, disfigurement,
and, rarely, splenic rupture. With early treatment, the majority
of patients are cured, but untreated cases can be fatal. Death is
usually secondary to bacterial infection of ulcerated lesions.
Toxoplasmosis
Toxoplasma gondii is an obligate intracellular parasite and
one of the most common human parasites in the world.258 Cats
are the definitive host for the organism. There are 3 forms of
the parasite: oocysts, trophozoites (tachyzoites, rapidly proliferating; or bradyzoites, slowly proliferating), and tissue cysts.
The noninfectious oocysts are excreted by the cat, and, in the
soil, if they are exposed to the right conditions, will grow into
infectious oocysts. The tachyzoites are the proliferating form

of the organism, and, when present in tissue, they incite an
acute inflammatory response and tissue necrosis. They cause
disease predominantly in immunocompromised hosts.258 The
slowly growing bradyzoites form into cysts. These cysts are
present late in infection and are associated with little, if any,
inflammatory response. Humans can become infected with T
gondii by ingesting material contaminated with infectious
oocysts or tissue cysts contained in raw or undercooked meat

B

❚Image 25❚ Leishmaniasis. A, Cutaneous leishmaniasis showing a diffuse superficial and deep dermal lymphocytic infiltrate
(H&E, ×5). B, High-power view shows the characteristic leishmanial organisms in histiocytes (H&E, ×100). Glass slides for
photographing provided by Rosalie Elenitsas, MD, Dermatopathology, University of Pennsylvania Medical Center, Philadelphia.

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