Bacterial, viral, fungal, and other infectious conditions

Clinical and radiographic findings

• This occurs in adults in the fifth and sixth decades of life, with equal sex predilection and equal jaw involvement, and patients are usually healthy.

• The most common manifestation is a periapical infection, painless (80% of cases) or painful, in a root canal–treated or grossly carious tooth. It may also be associated with impacted teeth, periodontal infection around natural teeth, periimplantitis around dental implants, and osteonecrosis and osteomyelitis of the jaws ( Fig. 4.1 A). Chronic untreated mandibular odontogenic infection may lead to cutaneous fistulae and cervicofacial actinomycosis (see Fig. 4.1 B).

  

• A sinus tract (gingival parulis) and suppuration are almost always present, and yellowish “sulfur granules” or “grains” representing masses of bacteria may be noted during the curettage ( Fig. 4.1 C–E).

• In periapical actinomycosis, there is a nondescript usually >1 cm radiolucency around a necrotic or endodontically treated tooth, a sign of long-standing infection, often associated with perforation of the buccal or lingual/palatal cortex ( Fig. 4.2 A–D).

  

• Pure soft tissue infections are rare and cases have been noted in the tongue.

• The presence of Actinomycetes colonies within tonsillar crypts may predispose patients to obstructive tonsillar hypertrophy but this is not considered a form of actinomycosis.

Etiopathogenesis and histopathologic features

Actinomycetes are non–spore-forming, gram-positive microaerophilic, obligate, or facultative filamentous bacteria. There are several species, such as Actinomyces israelii , A. odontolyticus, A. naeslundii, A. gerencseriae, A. viscosus , and A. meyeri. They cause suppurative lesions and enter the bone through a carious tooth, periodontal pockets, or possibly a sinus tract. Actinomycetes have been identified within root canals in 50% of infected root canals. The classic Splendore-Hoeppli effect composed of peripheral eosinophilic star-burst radiations represents deposition of antigen-antibody complexes (immunoglobulins and major basic proteins), inflammatory tissue debris, and fibrin. One theory suggests that this walling off of the bacteria prevents phagocytosis and destruction of the organisms leading to chronicity.

• Abundant granulation tissue is present with abscesses and acute and chronic inflammation. Concomitant radicular cyst, periapical granuloma, dentigerous cyst, or other pathosis is usually present.

• “Sulfur granules” are composed of round-to-ovoid masses of slender filamentous bacteria with a peripheral eosinophilic rim, often with eosinophilic star-burst appearance or radiating “clubs” (Splendore-Hoeppli phenomenon) surrounded by neutrophils ( Fig. 4.3 A–D). Clumps of actinomycetes alone without the eosinophilic fringe (representing the host response) are not sufficient for the diagnosis of active infection.

  

• Bacteria are gram-variable (gram-positive but with variable intensity of staining along the filament), and argyrophilic with methenamine silver stain (see Fig. 4.3 E–F).

• Positive culture for actinomyces is not sufficient for the diagnosis since this is a commensal in the biofilm of the teeth and will colonize the surfaces of exposed necrotic bone.

Differential diagnosis

• Actinomycotic colonies (without the eosinophilic border) are a common component of dental plaque that often contaminates oral biopsy specimens and do not represent actinomycosis in the absence of suppuration and clinical signs. It may also be seen within tonsilliths ( Fig. 4.3 G–H).

• Masses of actinomycotic organisms are often found on the surface of exposed bony sequestra, such as in osteoradionecrosis or medication-related osteonecrosis of the jaws. This phenomenon represents surface colonization only (biofilm) if sulfur granules are not noted on histopathology ( Fig. 17.8 ).

• Splendore-Hoeppli reaction is seen not only in actinomycosis but also in other bacterial infections such as botryomycosis, in deep fungal infections such as blastomycosis, and in parasitic infections such as schistosomiasis. Appropriate staining and attention to the morphology of the organism is essential for accurate diagnosis.

Management and prognosis

• Curettage, 2 to 3 weeks of antibiotics (e.g., amoxicillin, doxycycline, or clindamycin), and removal of the original source of infection (e.g., apical curettage and apicoectomy, extraction of carious or impacted tooth) is curative. Prolonged antibiotic therapy for several months is not required for conventional intraoral actinomycosis.

Clinical findings

• Primary herpetic gingivostomatitis: This is a common herpesvirus infection in the first three decades of life and most are subclinical infections. When symptomatic, there is a viral prodrome of fever, malaise, and sore throat, followed by an acute onset of multiple, painful, clustered, and subsequently coalescent ulcers on any mucosal surface, but frequently on the lip mucosa, tongue, and gingiva. Most cases are associated with herpes simplex virus (HSV)-1 and some with HSV-2 ( Fig. 4.4 A–B)

  

• Recrudescent infection in healthy hosts: Herpes labialis on the lip (fever blisters or cold sores) is the most common presentation with less common sites being the keratinized mucosa of the hard palatal mucosa and attached gingiva. There are painful, 2- to 3-mm clustered and coalescent ulcers with scalloped borders often induced by injury (e.g., sunburn) or trauma (e.g., dental procedures) (see Fig. 4.4 C–E).

• Recrudescent infection in immunocompromised hosts: Ulcers occur anywhere on the oral mucosa and may appear aphthous-like if on the nonkeratinized mucosa (see Fig. 4.4 F–H).

• More than 50% of cases of erythema multiforme are induced by HSV reactivation (see Chapter 8 ).

• Primary varicella-zoster virus (VZV): This infection causes vesicles on erythematous skin (“dew drop on a rose petal”) and also in the mouth that rupture to form ulcers. Reactivation of VZV tends to occur in older adults, in immunocompromised hosts, and in those on biologic therapies such as tumor necrosis factor inhibitors.

• Herpes zoster: This results in linear blisters and ulcers in a dermatomal distribution on the skin along the course of a sensory nerve, as well as in the oral cavity and facial skin corresponding to the distribution of the trigeminal nerve ( Fig. 4.5 ). Postherpetic neuropathy occurs frequently in older adults and can be chronic and debilitating.

  

Etiopathogenesis and histopathologic features

HSV and VZV are DNA viruses that are cytotoxic to epithelial cells. After primary infection, latency is established in sensory ganglia and peripherally at mucosal sites. Reactivation of HSV either leads to asymptomatic shedding, which is the primary means of transmission, or results in painful lesions as noted previously (also referred to as recrudescence ).

• Multinucleated giant epithelial cells are present superficially at the edge of the ulcer and exhibit “nuclear molding,” with nuclei containing “ground-glass” amphophilic Cowdry inclusions. Similar cells are noted if the edge of the ulcer is scraped (Tzanck test), and the presence of HSV or VZV may be confirmed by immunohistochemical studies ( Fig. 4.6 ).

  

• A biopsy of only the center of the ulcer without epithelium may not show viral inclusions and cannot be presumed to be negative for HSV or VZV infection.

• Positive polymerase chain reaction (PCR) test or culture for HSV should be correlated with clinical findings because asymptomatic shedding (induced by trauma, illness, or stress) is a frequent occurrence.

Differential diagnosis

• The epithelium adjacent to an ulcer may contain multinucleated giant epithelial cells, but these cells have abundant cytoplasm, no nuclear molding, dispersed chromatin, and no Cowdry inclusions, although nucleoli may be prominent ( Fig. 11.32 ). They tend to be within the suprabasal area of intact epithelium instead of superficially and immediately adjacent to the ulcer.

Management and prognosis

• Primary HSV infections, or recrudescent HSV infections in immunocompromised patients, as well as herpes zoster infections, are managed with supportive care, hydration, pain control, and systemic therapy with acyclovir, valacyclovir, or famciclovir (see Appendix B ).

• Herpes labialis may be successfully managed with a 1- or 2-day course of valacyclovir or famciclovir, topical acyclovir, penciclovir, or docosanol ( Appendix B ). The use of sunscreen often prevents recrudescent herpes labialis induced by sun damage.

Clinical findings

• Hairy leukoplakia occurs most commonly in immunocompromised individuals, especially those with HIV/AIDS with low CD4 counts and in organ transplant recipients.

• However, many cases have been reported in healthy patients, usually older adults, possibly due to immunosenescence, with a slight female predilection, unlike in patients with HIV/AIDS.

• Hairy leukoplakia presents as a white, painless, linear lesion or plaque, usually on the lateral border of tongue, and cases are usually bilateral. Classically, white linear lesions run perpendicular to the long axis of the tongue ( Fig. 4.7 ).

  

Etiopathogenesis and histopathologic features

EBV establishes latency in peripheral memory B lymphocytes and one theory proposes that these B lymphocytes migrate to the lamina propria or to the oral epithelium where EBV undergoes productive replication resulting in hairy leukoplakia. However, another theory is that EBV latently infects blood-borne Langerhans cell precursors which transport EBV to the oral epithelium where they mature into Langerhans cells and where productive replication occurs.

• There is variable parakeratosis and bacterial colonization may be present if the lesion has been traumatized; candidal hyphae and/or spores may be present, often in the absence of spongiotic pustules in immunocompromised hosts ( Figs. 4.8 and 4.9 A). Sharp demarcation of parakeratin from the underlying band of pale, edematous superficial keratinocytes is characteristic though not specific for the diagnosis.

  
  

• Virally infected cells within these pale keratinocytes show central Cowdry inclusions (“ground-glass,” homogeneous, amphophilic nuclear mass consisting of virions) with margination or “beading” of chromatin against the nuclear membrane (see Figs. 4.8 B and 4.9 B). Such findings are readily identified on exfoliative cytology. In situ hybridization studies show nuclear positivity for Epstein-Barr–encoded RNA (EBER); Epstein-Barr nucleic acid, and latent membrane protein (LMP) may be also positive (see Fig. 4.9 C).

• Ultrastructurally, there are herpesvirus-sized particles in the center of the nucleus (Cowdry inclusion) with chromatin margination at the periphery ( Fig. 4.9 D).

Differential diagnosis

• Factitial/frictional keratosis due to bite trauma does not show Cowdry inclusions or chromatin margination and is negative for EBV by in situ hybridization ( Fig. 4.10 ).

  

• Reactive epithelial atypia may be present and should not be over-diagnosed as dysplasia.

Management and prognosis

• Adjustment of antiretroviral therapy in patients with HIV/AIDS or reduction of immunosuppressive therapy in post-organ transplant patients may resolve lesions, and candidiasis should be treated ( Appendix B ).

• Since cases are usually asymptomatic, no treatment is necessary. However, cases have resolved with a combination of topical antiherpetic medications (such as 1% penciclovir or 5% acyclovir cream/ointment), valacyclovir, and 25% podophyllin resin.

• Hairy leukoplakia may be the first indication of HIV-positive status and patients should be tested if there are risk factors for HIV exposure in the patient’s history.

• Patients who are HIV negative should be reassured that this is not necessarily an indication of some other as yet undiagnosed immunosuppressive disorder.

Clinical findings

• Approximately 66% of patients are on iatrogenic immunosuppression for treatment of autoimmune diseases and post-organ transplantation with the most common medication being methotrexate in 46% of cases while 8% to 11% of patients are on azathioprine, mycophenolate, prednisone, rituximab and cyclosporine A; most of these patients are in the seventh decade of life. Females constitute 60% of patients probably because this condition is often seen in patients with rheumatoid arthritis which has a female predilection.

• The second most frequently affected population are older patients with age-related immunosenescence constituting 27% of cases and these patients are in the eighth decade of life.

• Less frequently affected patients are those undergoing cancer chemotherapy, those with HIV/AIDS, and those with primary immunodeficiency syndromes.

• It presents as a nonhealing, generally fairly large painful ulcer of the oral mucosa with the tongue and tonsils comprising 58% of cases ( Fig. 4.11 A).

  

• The gastrointestinal tract especially the anorectal region and the skin each comprise 20% of cases and the genital mucosa is infrequently affected; 17% exhibit multifocal disease.

Etiopathogenesis and histopathologic features

This is believed to arise from reactivation of latent EBV infection due to immunocompromise or immunosenescence. EBV latency typing reveals predominantly latency pattern II (as seen in Hodgkin lymphoma and nasopharyngeal carcinoma) with expression of genes for Epstein-Barr nuclear antigen (EBNA)-1 and LMP-1 and LMP-2.

• There is deep ulcer with a polymorphous infiltrate of lymphocytes, plasma cells, eosinophils, atypical immunoblast-like lymphocytes, and Hodgkin-like or Reed-Sternberg–like cells; the pattern may be diffuse or angiocentric ( Fig. 4.11 B–C).

• The atypical immunoblast-like lymphocytes and Hodgkin-like or Reed-Sternberg–like cells are CD30+, EBER+, and LMP+, and also positive for B-cell markers namely CD20, MUM-1, and PAX-5 ( Fig. 4.11 D–E). A small lymphocyte variant has been reported without the presence of atypical blast-like cells. There is variable positivity for CD79a, CD15, CD45, BCL-2, and BCL-6. PDL1 but not PD1 may be present within the atypical cells. There is a background of CD3+ T cells, usually around the atypical infiltrate, and focal necrosis may be present. Ki67 proliferation index in the EBER+ cells may be as high as 25%, and less than 25% in the EBER cells. There are at least 50 EBV+ cells/high power field in almost all cases.

• Some cases show polyclonal, oligoclonal, or clonal IgH and T-cell receptor gene rearrangements.

Differential diagnosis

• Traumatic ulcerative granuloma with stromal eosinophilia does not generally show atypical Reed-Sternberg cells but may have many eosinophils, lymphocytes, and histiocytes. Older reports of CD30+ traumatic ulcerative granulomas may have represented cases of EBV mucocutaneous ulcers.

• EBV-negative diffuse large B-cell lymphoma appears similar but consists of sheets of large, atypical lymphocytes and is not polymorphic as seen in EBV mucocutaneous ulcers; such lymphomas are CD30–, and positive for mutations such as MYD88 , CD79A , CD79B , CARD11 , and EZH2 which are not seen in EBV mucocutaneous ulcers.

• Classic Hodgkin lymphoma is positive for B-cell markers as well as being CD30+ and is also positive for EBV but this is a very rare occurrence in the oral cavity.