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Chapter Contents
Besides the common bacterial, fungal, and viral infections of the oral cavity, an infection that occurs in any part of the body may manifest in the mouth, including mycobacterial, treponemal, and protozoal infections, although they are uncommon and rarely occur initially in the mouth. In many parts of the world, syphilitic and protozoal infections are on the rise. Polymicrobial bacterial infections in the mouth are common and are generally not subject to biopsy, because most of these are related to dental caries and periodontal infections. Actinomycosis is one bacterial infection that is seen on biopsy with some frequency.
Actinomycosis
In the medical literature, the five common sites for actinomycosis are cervicofacial, pulmonary, ileocecal, genitourinary, and central nervous system. The least well-recognized, and yet fairly common, infection involving the jawbones and oral soft tissues is discussed here.
Clinical Findings
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This occurs in adults in the fifth and sixth decades of life, and patients are infrequently immunocompromised.
- •
The most common manifestation is a periapical radiolucency, painless (80% of cases) or painful, in a root canal–treated or grossly carious tooth ( Fig. 4.1A ). It may also be associated with impacted teeth, periodontitis around natural teeth, or periimplantitis around dental implants. Approximately 20% of cases involve the soft tissues only, and mandibular tooth infection may lead to cutaneous fistulae and cervicofacial actinomycosis (see Fig. 4.1B ).
FIG 4.1 (A) Periapical actinomycosis manifesting within an apical radicular cyst after root canal therapy. (B) Actinomycosis from a carious mandibular molar resulting in cutaneous sinus tract.(A, Courtesy Dr. Michael Joseph, private practice, Worcester, Mass.) - •
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. 4.2 ).
FIG 4.2 Periapical actinomycosis with yellow sulfur granules.(Courtesy Dr. Christopher Allen, private practice, Traverse City, Mich.) - •
The presence of actinomycetes colonies within tonsillar crypts may predispose patients to obstructive tonsillar hypertrophy; this is not considered a form of actinomycosis.
Etiopathogenesis and Histopathologic Features
Actinomyces are gram-positive microaerophilic, obligate, or facultative filamentous bacteria. There are several species, such as Actinomyces israelii (most common in infections), A. odontolyticus, A. naeslundii, A. gerencseriae, and A. viscosus. They cause suppurative lesions and enter the bone through a carious tooth or through periodontal pockets.
- •
Abundant granulation tissue is present with abscesses and acute and chronic inflammation.
- •
“Sulfur granules” are composed of round-to-ovoid masses of filamentous bacteria with a peripheral eosinophilic rim, often with eosinophilic radiating “clubs” (Splendore-Hoeppli phenomenon) surrounded by neutrophils ( Fig. 4.3A–B ). Bacteria are gram-positive, gram-variable (variable gram-positive staining along the filament), and argyrophilic (see Fig. 4.3C–D ).
FIG 4.3 Periapical actinomycosis. (A) Periapical granuloma and sulfur granule ( left ). (B) Sulfur granule with typical radiating morphology (Splendore-Hoeppli phenomenon) and suppuration. (C) Sulfur granule showing inconsistent Gram staining along the filament (Gram variability) (Brown and Brenn stain). (D) Sulfur granule containing slender argyrophilic filaments (methenamine silver stain). - •
Concomitant radicular cyst, periapical granuloma, dentigerous cyst, or other pathosis is usually present.
- •
Clumps of actinomycetes alone without the eosinophilic fringe (representing the host response) are not sufficient for the diagnosis.
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.
- •
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) (see Chapter 17 ).
Management and Prognosis
- •
Curettage, 2 to 3 weeks of antibiotics (eg, amoxicillin, doxycycline, or clindamycin), and removal of the original source of infection (eg, carious or impacted tooth) is curative. Prolonged antibiotic therapy is not indicated for conventional periapical actinomycosis.
References
Clinical Findings
- •
This occurs in adults in the fifth and sixth decades of life, and patients are infrequently immunocompromised.
- •
The most common manifestation is a periapical radiolucency, painless (80% of cases) or painful, in a root canal–treated or grossly carious tooth ( Fig. 4.1A ). It may also be associated with impacted teeth, periodontitis around natural teeth, or periimplantitis around dental implants. Approximately 20% of cases involve the soft tissues only, and mandibular tooth infection may lead to cutaneous fistulae and cervicofacial actinomycosis (see Fig. 4.1B ).
FIG 4.1 (A) Periapical actinomycosis manifesting within an apical radicular cyst after root canal therapy. (B) Actinomycosis from a carious mandibular molar resulting in cutaneous sinus tract.(A, Courtesy Dr. Michael Joseph, private practice, Worcester, Mass.) - •
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. 4.2 ).
FIG 4.2 Periapical actinomycosis with yellow sulfur granules.(Courtesy Dr. Christopher Allen, private practice, Traverse City, Mich.) - •
The presence of actinomycetes colonies within tonsillar crypts may predispose patients to obstructive tonsillar hypertrophy; this is not considered a form of actinomycosis.
Etiopathogenesis and Histopathologic Features
Actinomyces are gram-positive microaerophilic, obligate, or facultative filamentous bacteria. There are several species, such as Actinomyces israelii (most common in infections), A. odontolyticus, A. naeslundii, A. gerencseriae, and A. viscosus. They cause suppurative lesions and enter the bone through a carious tooth or through periodontal pockets.
- •
Abundant granulation tissue is present with abscesses and acute and chronic inflammation.
- •
“Sulfur granules” are composed of round-to-ovoid masses of filamentous bacteria with a peripheral eosinophilic rim, often with eosinophilic radiating “clubs” (Splendore-Hoeppli phenomenon) surrounded by neutrophils ( Fig. 4.3A–B ). Bacteria are gram-positive, gram-variable (variable gram-positive staining along the filament), and argyrophilic (see Fig. 4.3C–D ).
FIG 4.3 Periapical actinomycosis. (A) Periapical granuloma and sulfur granule ( left ). (B) Sulfur granule with typical radiating morphology (Splendore-Hoeppli phenomenon) and suppuration. (C) Sulfur granule showing inconsistent Gram staining along the filament (Gram variability) (Brown and Brenn stain). (D) Sulfur granule containing slender argyrophilic filaments (methenamine silver stain). - •
Concomitant radicular cyst, periapical granuloma, dentigerous cyst, or other pathosis is usually present.
- •
Clumps of actinomycetes alone without the eosinophilic fringe (representing the host response) are not sufficient for the diagnosis.
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.
- •
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) (see Chapter 17 ).
References
Herpesvirus Infections
Table 4.1 shows the eight herpesviruses that are pathogenic in humans. Primary infection is generally subclinical or results in only mild constitutional symptoms. All herpesviruses establish latency for the lifetime of the host after a primary infection, with periodic reactivation. Most adults in the United States are seropositive for many of the herpesviruses. Kaposi sarcoma is discussed in Chapter 6 .
| Herpesvirus Type | Disease Manifestation |
|---|---|
| HHV-1 Herpes simplex virus-1 Alpha virus |
Oral cavity: Primary herpetic gingivostomatitis and recrudescent herpes stomatitis or herpes labialis |
| Genital herpes, eczema herpeticum, herpes whitlow, herpes gladiatorum, ocular herpes, herpes encephalitis, disseminated infection | |
| HHV-2 Herpes simplex virus-2 Alpha virus |
Although usually found on skin and mucosa below the waist (genital herpes), may also be found in the mouth with lesions identical to those of HSV-1, neonatal infection, herpetic whitlow (also see HHV-1 above) |
| HHV-3 Varicella-zoster virus Alpha virus |
Oral cavity: Primary infection exhibits oral ulcers; recrudescent infection is facial or oral shingles along the distribution of the trigeminal nerve and is usually unilateral |
| Primary infection is chickenpox; skin shingles are common on the trunk | |
| HHV-4 Epstein-Barr virus Gamma virus |
Oral cavity: Hairy leukoplakia occurs in patients with HIV/AIDS, organ transplant recipients, or other immunocompromised hosts, as well as those on immunosuppressive agents; rarely occurs in the healthy host Epstein-Barr virus mucocutaneous ulcer in immunosuppressed or immunosenescent host |
| Infectious mononucleosis, Burkitt lymphoma, nasopharyngeal carcinoma, central nervous system lymphoma, post-transplant lymphoproliferative disorder, Hodgkin lymphoma, plasmablastic lymphoma | |
| HHV-5 Cytomegalovirus Beta virus |
Oral cavity: Penetrating oral ulcers; organism may be a bystander noted in other ulcerative lesions |
| Infectious mononucleosis–like syndrome, retinitis, gastroenteritis, hepatitis, pneumonitis | |
| HHV-6 Beta virus |
No documented oral findings |
| Roseola infantum, exanthema subitum | |
| HHV-7 Beta virus |
No documented oral findings |
| Roseola infantum, exanthema subitum | |
| HHV-8 Kaposi sarcoma herpesvirus Gamma virus |
Oral cavity: Kaposi sarcoma |
| Skin and visceral Kaposi sarcoma, primary effusion lymphoma, multicentric Castleman disease |
Herpes Simplex Virus and Varicella Zoster Infection
These two herpesvirus infections result in painful ulcers and blisters of the oral mucosa and skin.
Clinical Findings
- •
Primary herpetic gingivostomatitis is the most common herpesvirus infection in the first three decades of life. There is a viral prodrome 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. 4.4A–B )
FIG 4.4 Herpes simplex virus infection. (A) Primary infection with coalescent ulcers on the tongue dorsum. (B) Ulcers on the nonkeratinized lip mucosa and marginal gingiva of same patient as in A. (C) Recrudescent herpes labialis in immunocompetent host. (D) Recrudescent herpes simplex on the marginal gingiva in an immunocompetent host. (E) Recrudescent herpes simplex on the hard palatal mucosa. (F) Recrudescent herpes simplex virus ulcer of the ventral tongue and skin in a patient with cancer. - •
Recrudescent infection in healthy hosts: herpes labialis (fever blisters or cold sores) on the lip is the most common presentation; less common sites are 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 (eg, sunburn) or trauma (eg, dental procedures) (see Fig. 4.4C–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. 4.4F ).
- •
At least 70% of cases of erythema multiforme are induced by HSV reactivation (see Chapter 8 ).
- •
Primary varicella-zoster virus (VZV) infection exhibits vesicles on the skin 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 new biologic therapies such as tumor necrosis factor inhibitors.
- •
Herpes zoster is present as 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 and can be chronic and debilitating.
FIG 4.5 Recrudescent varicella zoster infection: oral shingles exhibiting coalescent ulcers of the right hard palatal mucosa.
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 leads to asymptomatic shedding, which is the primary means of transmission. Some reactivations present with painful lesions as noted above (also referred to as recrudescence ).
- •
Multinucleated giant epithelial cells at the edge of the ulcer exhibit “nuclear molding,” and there is acute and chronic inflammation. Nuclei contain “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 ).
FIG 4.6 Herpes simplex virus (HSV) infection. (A) Oral mucosa with ulceration and hematoxyphilic cells at the ulcer edge. (B) Multinucleated epithelial cells with nuclear molding and Cowdry inclusions. (C) Immunohistochemical study confirms the presence of HSV-1. - •
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 cultures for HSV should be correlated with clinical findings because asymptomatic shedding (induced by trauma, illness, or stress) is a frequent occurrence.
Differential Diagnosis
- •
Inflammatory reactions and 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 (see Chapter 11 ).
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.
References
Herpes Simplex Virus and Varicella Zoster Infection
These two herpesvirus infections result in painful ulcers and blisters of the oral mucosa and skin.
Clinical Findings
- •
Primary herpetic gingivostomatitis is the most common herpesvirus infection in the first three decades of life. There is a viral prodrome 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. 4.4A–B )
FIG 4.4 Herpes simplex virus infection. (A) Primary infection with coalescent ulcers on the tongue dorsum. (B) Ulcers on the nonkeratinized lip mucosa and marginal gingiva of same patient as in A. (C) Recrudescent herpes labialis in immunocompetent host. (D) Recrudescent herpes simplex on the marginal gingiva in an immunocompetent host. (E) Recrudescent herpes simplex on the hard palatal mucosa. (F) Recrudescent herpes simplex virus ulcer of the ventral tongue and skin in a patient with cancer. - •
Recrudescent infection in healthy hosts: herpes labialis (fever blisters or cold sores) on the lip is the most common presentation; less common sites are 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 (eg, sunburn) or trauma (eg, dental procedures) (see Fig. 4.4C–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. 4.4F ).
- •
At least 70% of cases of erythema multiforme are induced by HSV reactivation (see Chapter 8 ).
- •
Primary varicella-zoster virus (VZV) infection exhibits vesicles on the skin 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 new biologic therapies such as tumor necrosis factor inhibitors.
- •
Herpes zoster is present as 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 and can be chronic and debilitating.
FIG 4.5 Recrudescent varicella zoster infection: oral shingles exhibiting coalescent ulcers of the right hard palatal mucosa.
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 leads to asymptomatic shedding, which is the primary means of transmission. Some reactivations present with painful lesions as noted above (also referred to as recrudescence ).
- •
Multinucleated giant epithelial cells at the edge of the ulcer exhibit “nuclear molding,” and there is acute and chronic inflammation. Nuclei contain “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 ).
FIG 4.6 Herpes simplex virus (HSV) infection. (A) Oral mucosa with ulceration and hematoxyphilic cells at the ulcer edge. (B) Multinucleated epithelial cells with nuclear molding and Cowdry inclusions. (C) Immunohistochemical study confirms the presence of HSV-1. - •
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 cultures for HSV should be correlated with clinical findings because asymptomatic shedding (induced by trauma, illness, or stress) is a frequent occurrence.
Differential Diagnosis
- •
Inflammatory reactions and 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 (see Chapter 11 ).
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
- •
Primary herpetic gingivostomatitis is the most common herpesvirus infection in the first three decades of life. There is a viral prodrome 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. 4.4A–B )
FIG 4.4 Herpes simplex virus infection. (A) Primary infection with coalescent ulcers on the tongue dorsum. (B) Ulcers on the nonkeratinized lip mucosa and marginal gingiva of same patient as in A. (C) Recrudescent herpes labialis in immunocompetent host. (D) Recrudescent herpes simplex on the marginal gingiva in an immunocompetent host. (E) Recrudescent herpes simplex on the hard palatal mucosa. (F) Recrudescent herpes simplex virus ulcer of the ventral tongue and skin in a patient with cancer. - •
Recrudescent infection in healthy hosts: herpes labialis (fever blisters or cold sores) on the lip is the most common presentation; less common sites are 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 (eg, sunburn) or trauma (eg, dental procedures) (see Fig. 4.4C–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. 4.4F ).
- •
At least 70% of cases of erythema multiforme are induced by HSV reactivation (see Chapter 8 ).
- •
Primary varicella-zoster virus (VZV) infection exhibits vesicles on the skin 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 new biologic therapies such as tumor necrosis factor inhibitors.
- •
Herpes zoster is present as 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 and can be chronic and debilitating.
FIG 4.5 Recrudescent varicella zoster infection: oral shingles exhibiting coalescent ulcers of the right hard palatal mucosa.
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 leads to asymptomatic shedding, which is the primary means of transmission. Some reactivations present with painful lesions as noted above (also referred to as recrudescence ).
- •
Multinucleated giant epithelial cells at the edge of the ulcer exhibit “nuclear molding,” and there is acute and chronic inflammation. Nuclei contain “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 ).
FIG 4.6 Herpes simplex virus (HSV) infection. (A) Oral mucosa with ulceration and hematoxyphilic cells at the ulcer edge. (B) Multinucleated epithelial cells with nuclear molding and Cowdry inclusions. (C) Immunohistochemical study confirms the presence of HSV-1. - •
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 cultures for HSV should be correlated with clinical findings because asymptomatic shedding (induced by trauma, illness, or stress) is a frequent occurrence.
Differential Diagnosis
- •
Inflammatory reactions and 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 (see Chapter 11 ).
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.
References
Hairy Leukoplakia
Hairy leukoplakia is caused by the Epstein-Barr virus (EBV), and the term leukoplakia as used in this context does not connote any tendency for dysplasia or malignancy.
Clinical Findings
- •
Hairy leukoplakia occurs most commonly in immunocompromised individuals, especially those with HIV/AIDS with low CD4 counts, in organ transplant recipients, and in patients on steroid inhalers. Cases have been reported in healthy patients, usually older adults, possibly due to immunosenescence.
- •
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 ).
FIG 4.7 Hairy leukoplakia. (A) Typical vertical fissures on lateral border of tongue. (B) White plaque and fissures, likely with secondary candidiasis.
Etiopathogenesis and Histopathologic Features
EBV establishes latency in peripheral blood pre-Langerhans cells that migrate into the epithelium as Langerhans cells, where the virus is reactivated and leads to productive replication.
- •
There is variable parakeratosis with or without bacterial colonization, similar to factitial keratosis; candidal hyphae and/or spores are present, often in the absence of spongiotic pustules ( Figs. 4.8 and 4.9A ).
FIG 4.8 Hairy leukoplakia. (A) Oral mucosa with parakeratosis and acanthosis. (B) There is candidal colonization without spongiotic pustules and keratinocytes exhibit peripheral condensation of chromatin surrounding smudgy central Cowdry inclusions.
FIG 4.9 Hairy leukoplakia. (A) Oral mucosa with parakeratosis and underlying band of pale, ballooned cells. (B) Keratinocytes exhibit peripheral condensation of chromatin, coarsely clumped chromatin, and smudgy Cowdry inclusions. (C) In situ hybridization study shows nuclear positivity for Epstein-Barr virus–encoded mRNA. (D) Electron photomicrograph showing peripheral condensation of chromatin (“beading”) and nucleus filled with virions that constitute the Cowdry inclusion. - •
Sharp demarcation of parakeratin from the subjacent pale, edematous superficial keratinocytes is characteristic. Virally infected cells show central Cowdry inclusions (“ground-glass,” homogeneous, amphophilic nuclear mass consisting of virions) with margination (“beading”) of chromatin against the nuclear membrane (see Figs. 4.8B and 4.9B ). 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. 4.9C ).
- •
Ultrastructurally, there are herpesvirus-sized particles in the center of the nucleus (Cowdry inclusion) with chromatin margination at the periphery ( Fig. 4.9D ).
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 ).
FIG 4.10 Frictional/factitial parakeratosis. (A) Oral mucosa with parakeratosis and underlying band of pale cells and acanthosis. (B) There is no evidence of Cowdry inclusions or chromatin margination can be seen.
Management and Prognosis
- •
Adjustment of antiretroviral therapy or reduction of immunosuppressive therapy in post–organ transplant patients may resolve lesions, and candidiasis should be treated ( Appendix B ).
- •
Cases may resolve 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.
References
Clinical Findings
- •
Hairy leukoplakia occurs most commonly in immunocompromised individuals, especially those with HIV/AIDS with low CD4 counts, in organ transplant recipients, and in patients on steroid inhalers. Cases have been reported in healthy patients, usually older adults, possibly due to immunosenescence.
- •
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 ).
FIG 4.7 Hairy leukoplakia. (A) Typical vertical fissures on lateral border of tongue. (B) White plaque and fissures, likely with secondary candidiasis.
Etiopathogenesis and Histopathologic Features
EBV establishes latency in peripheral blood pre-Langerhans cells that migrate into the epithelium as Langerhans cells, where the virus is reactivated and leads to productive replication.
- •
There is variable parakeratosis with or without bacterial colonization, similar to factitial keratosis; candidal hyphae and/or spores are present, often in the absence of spongiotic pustules ( Figs. 4.8 and 4.9A ).
FIG 4.8 Hairy leukoplakia. (A) Oral mucosa with parakeratosis and acanthosis. (B) There is candidal colonization without spongiotic pustules and keratinocytes exhibit peripheral condensation of chromatin surrounding smudgy central Cowdry inclusions.
FIG 4.9 Hairy leukoplakia. (A) Oral mucosa with parakeratosis and underlying band of pale, ballooned cells. (B) Keratinocytes exhibit peripheral condensation of chromatin, coarsely clumped chromatin, and smudgy Cowdry inclusions. (C) In situ hybridization study shows nuclear positivity for Epstein-Barr virus–encoded mRNA. (D) Electron photomicrograph showing peripheral condensation of chromatin (“beading”) and nucleus filled with virions that constitute the Cowdry inclusion. - •
Sharp demarcation of parakeratin from the subjacent pale, edematous superficial keratinocytes is characteristic. Virally infected cells show central Cowdry inclusions (“ground-glass,” homogeneous, amphophilic nuclear mass consisting of virions) with margination (“beading”) of chromatin against the nuclear membrane (see Figs. 4.8B and 4.9B ). 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. 4.9C ).
- •
Ultrastructurally, there are herpesvirus-sized particles in the center of the nucleus (Cowdry inclusion) with chromatin margination at the periphery ( Fig. 4.9D ).
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 ).
FIG 4.10 Frictional/factitial parakeratosis. (A) Oral mucosa with parakeratosis and underlying band of pale cells and acanthosis. (B) There is no evidence of Cowdry inclusions or chromatin margination can be seen.
Management and Prognosis
- •
Adjustment of antiretroviral therapy or reduction of immunosuppressive therapy in post–organ transplant patients may resolve lesions, and candidiasis should be treated ( Appendix B ).
- •
Cases may resolve 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.
References
Epstein-Barr Virus Mucocutaneous Ulcer
Clinical Findings
- •
This occurs in patients on immunosuppressive medications for autoimmune diseases (such as methotrexate for rheumatoid arthritis), in post–organ transplant patients, and in patients in the eighth decade of life and older (age-related immunosenescence).
- •
It presents as a nonhealing ulcer of the oral mucosa (tongue and tonsils are most common sites), skin, or gastrointestinal tract.
Etiopathogenesis and Histopathologic Features
This is believed to arise from reactivation of latent EBV infection due to immunocompromise or immunosenescence.
- •
There is deep ulcer with a polymorphous infiltrate of lymphocytes, plasma cells, eosinophils, atypical immunoblast-like lymphocytes, and Hodgkin-like cells or Reed-Sternberg–like cells ( Fig. 4.11A–B )
FIG 4.11 Epstein-Barr virus mucocutaneous ulcer. (A) Ulcerated mucosa with an intense, deep lymphocytic infiltrate. (B) The infiltrate is polymorphous and contains atypical Hodgkin-like cells with convoluted nuclear outlines. (C) Lymphocytes are positive for CD30 and CD20 ( inset , CD20). (D) Lymphocytes are positive for Epstein-Barr–encoded RNA.(Courtesy Dr. Indraneel Bhattacharyya, University of Florida, Gainesville, Fla.) - •
There are sheets of CD20+ cells also positive for CD30, MUM-1, and PAX-5. Atypical cells are CD20-, EBER-, and LMP1+ and occasionally CD15-, CD45-, Bcl-2 and Bcl-6 ( Fig. 4.11C–D ). The infiltrate is CD10- and BCL6−, and scattered CD3 cells are present, often in a band at the base of the ulcer.
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Some cases show light chain restriction or T-cell receptor gene rearrangements or other restricted T-cell responses.
Differential Diagnosis
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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 been cases of EBV mucocutaneous ulcers.
Management and Prognosis
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Reduction in immunosuppressive therapy regresses lesions, and cases associated with immunosenescence often show spontaneous regression. Some cases require treatment with chemotherapy, radiation, mycophenolate mofetil, or rituximab, and none have resulted in disease-related death.
References
Clinical Findings
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This occurs in patients on immunosuppressive medications for autoimmune diseases (such as methotrexate for rheumatoid arthritis), in post–organ transplant patients, and in patients in the eighth decade of life and older (age-related immunosenescence).
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It presents as a nonhealing ulcer of the oral mucosa (tongue and tonsils are most common sites), skin, or gastrointestinal tract.
Etiopathogenesis and Histopathologic Features
This is believed to arise from reactivation of latent EBV infection due to immunocompromise or immunosenescence.
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There is deep ulcer with a polymorphous infiltrate of lymphocytes, plasma cells, eosinophils, atypical immunoblast-like lymphocytes, and Hodgkin-like cells or Reed-Sternberg–like cells ( Fig. 4.11A–B )
FIG 4.11 Epstein-Barr virus mucocutaneous ulcer. (A) Ulcerated mucosa with an intense, deep lymphocytic infiltrate. (B) The infiltrate is polymorphous and contains atypical Hodgkin-like cells with convoluted nuclear outlines. (C) Lymphocytes are positive for CD30 and CD20 ( inset , CD20). (D) Lymphocytes are positive for Epstein-Barr–encoded RNA.(Courtesy Dr. Indraneel Bhattacharyya, University of Florida, Gainesville, Fla.) - •
There are sheets of CD20+ cells also positive for CD30, MUM-1, and PAX-5. Atypical cells are CD20-, EBER-, and LMP1+ and occasionally CD15-, CD45-, Bcl-2 and Bcl-6 ( Fig. 4.11C–D ). The infiltrate is CD10- and BCL6−, and scattered CD3 cells are present, often in a band at the base of the ulcer.
- •
Some cases show light chain restriction or T-cell receptor gene rearrangements or other restricted T-cell responses.
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 been cases of EBV mucocutaneous ulcers.
Management and Prognosis
- •
Reduction in immunosuppressive therapy regresses lesions, and cases associated with immunosenescence often show spontaneous regression. Some cases require treatment with chemotherapy, radiation, mycophenolate mofetil, or rituximab, and none have resulted in disease-related death.
References
Cytomegalovirus Infection
Clinical Findings
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Neonates and immunocompromised individuals are generally affected, especially those with HIV/AIDS or organ transplant (especially kidney and hematopoietic stem cell transplant) recipients. Serious morbidities include retinitis, gastrointestinal ulcers, encephalitis, hepatitis, and pneumonitis.
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This occurs as a large, usually solitary, painful ulcer on the oral mucosa ( Fig. 4.12 ). Cytomegalovirus (CMV) antigenemia may be present.
FIG 4.12 Cytomegalovirus-infected ulcer of the left ventral tongue.
Etiopathogenesis and Histopathologic Features
Smooth muscle cells, endothelial cells, myeloid precursor cells, and immature Langerhans cells of the mucosa are sites of latency and replication. CMV-infected cells may also represent an incidental finding (“passenger”) in an ulcer caused by another agent, such as HSV, and may be seen in clinically normal skin.
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Mucosal ulceration is present, and large, ballooned cells are noted within the endothelium or stromal cells. These cells contain “owl-eye” nuclei because of prominent eosinophilic nucleoli as well as dark pink granules in the cytoplasm ( Fig. 4.13A–C ). Biopsies must be of sufficient depth for diagnosis.
FIG 4.13 Cytomegalovirus (CMV) infection. (A) The oral mucosa is ulcerated (ulcer at bottom ). (B) Ballooned cells with large nuclei and prominent red nucleoli (“owl eye”), as well as slightly granular amphophilic cytoplasm, can be seen. (C) There is involvement of endothelial cells by CMV. (D) In situ hybridization study positive for CMV. - •
In situ hybridization studies for CMV show nuclear positivity (see Fig. 4.13D ).
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Quantitative polymerase chain reaction (PCR) on blood samples, as well as CMV antigenemia (pp65 antigen in leukocytes), is helpful in diagnosis.
Differential Diagnosis
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EBV-associated mucocutaneous ulcers exhibit atypical, large, immunoblast-like B cells and Reed-Sternberg–like cells that are EBER- and CD30+.
Management and Prognosis
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Ganciclovir and valganciclovir are the conventional treatments; newer medications include letermovir and maribavir.
References
Clinical Findings
- •
Neonates and immunocompromised individuals are generally affected, especially those with HIV/AIDS or organ transplant (especially kidney and hematopoietic stem cell transplant) recipients. Serious morbidities include retinitis, gastrointestinal ulcers, encephalitis, hepatitis, and pneumonitis.
- •
This occurs as a large, usually solitary, painful ulcer on the oral mucosa ( Fig. 4.12 ). Cytomegalovirus (CMV) antigenemia may be present.
FIG 4.12 Cytomegalovirus-infected ulcer of the left ventral tongue.
Etiopathogenesis and Histopathologic Features
Smooth muscle cells, endothelial cells, myeloid precursor cells, and immature Langerhans cells of the mucosa are sites of latency and replication. CMV-infected cells may also represent an incidental finding (“passenger”) in an ulcer caused by another agent, such as HSV, and may be seen in clinically normal skin.
- •
Mucosal ulceration is present, and large, ballooned cells are noted within the endothelium or stromal cells. These cells contain “owl-eye” nuclei because of prominent eosinophilic nucleoli as well as dark pink granules in the cytoplasm ( Fig. 4.13A–C ). Biopsies must be of sufficient depth for diagnosis.
FIG 4.13 Cytomegalovirus (CMV) infection. (A) The oral mucosa is ulcerated (ulcer at bottom ). (B) Ballooned cells with large nuclei and prominent red nucleoli (“owl eye”), as well as slightly granular amphophilic cytoplasm, can be seen. (C) There is involvement of endothelial cells by CMV. (D) In situ hybridization study positive for CMV. - •
In situ hybridization studies for CMV show nuclear positivity (see Fig. 4.13D ).
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Quantitative polymerase chain reaction (PCR) on blood samples, as well as CMV antigenemia (pp65 antigen in leukocytes), is helpful in diagnosis.
References
Human Papillomavirus–Related Benign Lesions
Squamous papilloma, verruca vulgaris, condyloma acuminatum, and Heck disease (focal epithelial hyperplasia) are discussed together because of their similarities in clinical presentation and histopathology.
Clinical Findings
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These tend to occur in young patients, and all present as painless, exophytic, papillary/verrucous or papular, white or pink, sessile or pedunculated growths on the mucosa.
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Squamous papilloma: this is often seen on the soft palate or tongue and may be white or pink ( Fig. 4.14A ).
FIG 4.14 (A) Squamous papilloma of the left ventral tongue. (B) Verruca vulgaris of the right hard palatal mucosa. (C) Condyloma acuminatum (one of many) in a patient after lung transplant. (D) Condyloma acuminata in a patient with HIV/AIDS. (E) Pedunculated condyloma acuminatum in a healthy patient. (F) Heck disease in a child from Guatemala.(A, Courtesy Dr. Mark Lerman, Lecturer, Harvard School of Dental Medicine, Boston, Mass; B, Courtesy Dr. John Lovas, Dalhousie University, Halifax, Nova Scotia, Canada; D, Courtesy Dr. Mark Lerman, Harvard School of Dental Medicine, Boston, Mass; E, Courtesy Dr. Sherwin Kershman, private practice, Houston, Tex; F, Courtesy Dr. Roman Carlos, Guatemala City, Guatemala.) - •
Verruca vulgaris: this is often on the gingiva, lips, and palatal mucosa and is almost always white ( Fig. 4.14B ).
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Condyloma acuminatum: this is usually seen in immunocompromised patients (and sometimes in immunocompetent patients) as single or multiple papular or papillary lesions ( Fig. 4.14C–E ).
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Heck disease: there are multiple papules/nodules or papillary lesions (less common) on the mucosa of the lips and tongue, often seen in young persons (first and second decades of life) living in crowded conditions in South and Central America, with a prevalence of up to 13%. It is also common in Africa, the Middle East, in patients with HIV/AIDS, and sporadically in North America (see Fig. 4.14F ). The condition tends to regress with age.
Etiopathogenesis and Histopathologic Features
These lesions are related to human papillomavirus infection. In situ hybridization and PCR studies have allowed these to be characterized more accurately. Condylomas may result from sexual transmission, vertical transmission (maternal-fetal), or through salivary transmission.
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See Table 4.2 and Figs. 4.15–4.25 for histopathologic features.
