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 Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 35 DOI: 10.1309/6BBT12WGNK77N4EH 35 35 Montone / HEAD AND NECK INFECTIONS 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 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 36 36 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH 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 to months but may persist for as long as 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 © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE 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 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 Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 37 DOI: 10.1309/6BBT12WGNK77N4EH 37 37 Montone / HEAD AND NECK INFECTIONS 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) 38 38 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH ❚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 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 © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE 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 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 Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 39 DOI: 10.1309/6BBT12WGNK77N4EH 39 39 Montone / HEAD AND NECK INFECTIONS A B ❚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 40 40 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH 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 © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE C D E F spontaneously in to weeks Secondary syphilis develops about 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 Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 41 DOI: 10.1309/6BBT12WGNK77N4EH 41 41 Montone / HEAD AND NECK INFECTIONS 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) C 42 42 “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 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 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE weapon There are 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 A C 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 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 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 Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 43 DOI: 10.1309/6BBT12WGNK77N4EH 43 43 Montone / HEAD AND NECK INFECTIONS 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) 44 44 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE 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 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) Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 53 DOI: 10.1309/6BBT12WGNK77N4EH 53 53 Montone / HEAD AND NECK INFECTIONS 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 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 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 54 54 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH 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 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 © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE 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 to 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 HHV-6 is a virus that most commonly infects the oropharynx in early childhood Disease is characterized Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 55 DOI: 10.1309/6BBT12WGNK77N4EH 55 55 Montone / HEAD AND NECK INFECTIONS 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 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 (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 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) 56 56 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH 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 © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE A B C D E ❚Image 23❚ Human herpesvirus (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 in KS showing nuclear staining in the vascular endothelial cells (diaminobenzidine/hematoxylin counterstain, ×50) Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 57 DOI: 10.1309/6BBT12WGNK77N4EH 57 57 Montone / HEAD AND NECK INFECTIONS 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 58 58 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH 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 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 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 © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE 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 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 Am J Clin Pathol 2007;128:35-67 © American Society for Clinical Pathology 59 DOI: 10.1309/6BBT12WGNK77N4EH 59 59 Montone / HEAD AND NECK INFECTIONS from an intermediate host Human to human transmission can only occur from mother to fetus through a transplacental route In immunocompetent hosts, most cases are benign The most severe symptoms occur in congenital disease and in immunocompromised hosts The most common head and neck manifestation of T gondii infection is cervical lymphadenopathy.259 Histologically, lymph nodes show follicular hyperplasia associated with monocytoid B-cell hyperplasia and clusters of epithelioid histiocytes and loosely formed nonnecrotizing granulomas ❚Image 26A❚ Individual organisms are almost never found, but cysts containing organisms may rarely be observed If organisms are prominent, the patient is most likely immunosuppressed The differential diagnosis includes Hodgkin disease, mononucleosis, and Whipple disease Recent reports have shown the diagnosis of T gondii lymphadenitis using FNA biopsy of infected lymph nodes.260 Another important head and neck manifestation of T gondii is ocular involvement Ocular toxoplasmosis occurs from activation of cysts deposited in the retina and is manifested by retinal A B C D ❚Image 26❚ Toxoplasma gondii A, Cervical lymph node biopsy specimen from a patient with confirmed T gondii by serologic testing Follicular hyperplasia, monocytoid B-cell hyperplasia, and collections of epithelioid histiocytes are shown (H&E, ×25) Organisms are rarely identified in toxoplasmosis lymphadenitis, especially in immunocompetent patients B, T gondii encephalitis in an HIV+ patient There are extensive necrosis and cysts containing the organisms (H&E, ×50) C, Higher power view of T gondii encephalitis showing individual tachyzoites in the areas of necrosis (H&E, ×100) D, In situ hybridization for T gondii ribosomal RNA highlights the tachyzoites in the tissue (diaminobenzidine/hematoxylin counterstain, ×100) The presence of tachyzoites is an indication of active infection The cysts may persist for years after infection, and their presence in tissue does not confirm active disease 60 60 Am J Clin Pathol 2007;128:35-67 DOI: 10.1309/6BBT12WGNK77N4EH © American Society for Clinical Pathology Microbiology and Infectious Disease / REVIEW ARTICLE necrosis Most cases of ocular toxoplasmosis are the result of congenital infection, so clinical manifestation in adults usually represents reactivation of latent infection Reactivation of infection was recently reported following laser eye surgery.261 The diagnosis of toxoplasmosis is often made by identifying the organisms within tissue samples ❚Image 26B❚ In addition, diagnosis of disseminated disease may be made by examination of sputum.262 Tachyzoites and cysts are often seen on H&E stain ❚Image 26C❚ PAS stain can also highlight the organisms Disseminated disease has been diagnosed by examination of sputum smears The presence of rare cysts should be correlated with the clinical findings because cysts may just represent latent infection Immunohistochemical analysis, in situ hybridization, and PCR have all been used to diagnose infection ❚Image 26D❚.263-265 The prognosis is good except in immunocompromised people Mimics of Infections Myospherulosis Myospherulosis is a rare entity resulting from phagocytosis of parts of RBCs by macrophages.266 The entity is usually seen following surgeries that use petroleum-based antibiotic ointment The macrophages containing the portions of cells histologically resemble the endospores of Coccidioides or macrophages containing fungal forms such as Histoplasma or Cryptococcus The histiocytic particles are negative for silver and PAS stains Vasculitis Vasculitides in the head and neck area may histologically mimic infections.267 Necrotizing vasculitis may overlap with features of angioinvasive fungal infections Special stains highlight the organisms, and the “vasculitis” seen is secondary to the fungal infection Another vasculitis that mimics infection is Wegener granulomatosis, which is characterized by granulomatous vasculitis with zones of necrosis Infectious agents such as acid-fast organisms, some other bacterial infections, and fungal infections can manifest with similar histologic findings Elastic stains to confirm the granulomatous infiltrate centered around blood vessels should aid in the distinction between Wegener granulomatosis and infection Special stains for organisms should be performed to rule out infection when one is dealing with histologic features suspected to represent Wegener granulomatosis Although vasculitis syndromes often mimic infections, there is a strong possibility that many of these diseases result from infectious processes, particularly unknown viruses.268 From the Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia Address reprint requests to Dr Montone: Dept of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, 3400 Spruce St, Founders, Philadelphia, PA 19104 References Brook I Chronic sinusitis in children and adults: role of bacteria and antimicrobial management Curr Allergy Asthma Rep 2005;5:482-490 Biel MA, Brown CA, Levinson RM Evaluation of the microbiology of chronic 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2005;19:458-461 11 DelGaudio JM Direct nasopharyngeal reflux of gastric acid is a contributing factor in refractory chronic rhinosinusitis Laryngoscope 2005;115:946-957 12 Perloff JR, Palmer JN Evidence of bacterial biofilms in a rabbit model of sinusitis Am J Rhinol 2005;19:1-6 13 Sanderson AR, Leid JG, Hunsaker D Bacterial biofilms on the sinus mucosa of human subjects with chronic rhinosinusitis Laryngoscope 2006;116:1121-1126 14 Tewfik TL, Al Garni M Tonsillopharyngitis: clinical highlights J Otolaryngol 2005;34(suppl 1):S45-S49 15 Dell’Aringa AR, Juares AJ, Melo C, et al Histological analysis of tonsillectomy and adenoidectomy specimens: January 2001 to May 2003 Rev Bras Otorrinolaringol (Engl Ed) 2005;71:18-22 16 Dost P Histological examination following adenoidectomy and tonsillectomy in children: surprising results are very rare HNO 2006;54:16-19 17 Cockerell CJ, Connor DH Cat scratch disease In: Connor DH, Chandler FW, Schwartz DA, et al, eds Pathology of Infectious Diseases 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is often seen in the jaw area, Actinomyces... 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... 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