Oral Pathology 1st lecture Dr. SAMEEM M.BAKER

Vesiculobullous Diseases

VIRAL DISEASE

Herpes Simplex Infection

Varicella-Zoster Infection

Hand-Foot-and-Mouth Disease

Herpangina

Measles (Rubeola)

IMMUNOLOGIC DISEASE

Pemphigus Vulgaris

Mucous Membrane Pemphigoid

Bullous Pemphigoid

Dermatitis Herpetiformis

Linear Immunoglobulin A Disease (LAD)

HEREDITARY DISEASE

Epidermolysis Bullosa

VIRAL DISEASE

Oral mucous membranes may be infected by one of several

different viruses, each producing a relatively distinct clinical

pathologic picture.

The herpes viruses are a large family of viruses characterized by a

DNA core surrounded by a capsid and an envelope. Seven types of

herpes viruses are known to be pathogenic for humans, with six of

these linked to diseases in the head and neck area.

Herpes Simplex Infection

Herpes simplex virus (HSVs) infections are common vesicular

eruptions of the skin and mucosa. They occur in two forms:

primary (systemic) and secondary (localized) and may be localized

or secondary in nature. Both forms are self-limited, but

recurrences of the secondary form are common because the virus

can be sequestered within ganglionic tissue in a latent state.

Control of symptoms rather than cure is the usual goal of

treatment.

Pathogenesis

Physical contact with an infected individual or with body fluids

is the typical route of HSV inoculation.

Transmission for a seronegative individual who has not been

previously exposed to the virus.

Someone with a low titer of protective antibody to HSV.

The incubation period after exposure ranges from several days to 2

weeks. In overt primary disease, a vesiculo-ulcerative eruption

(primary gingivostomatitis) typically occurs in the oral and

perioral tissues. The focus of eruption is expected at the original

site of contact.

After resolution of primary herpetic gingivostomatitis, the virus is

believed to migrate, through some unknown mechanism, along the

periaxon sheath of the trigeminal nerve to the trigeminal ganglion,

where it is capable of remaining in a latent or sequestered state.

During latency, no infectious virus is produced.

Primary Herpetic Gingivostomatitis:

Seen in children, although adults who have not been previously

exposed to HSV. By age 15, about half the population is

infected.

The vesicular eruption appears on the skin, vermilion, and oral

mucous membranes.

Intraoral, lesions may appear on any mucosal surface.

The lesions are confined to the lips, hard palate, and gingiva.

The primary lesions are accompanied by fever, arthralgia,

malaise, anorexia, headache, and cervical lymphadenopathy. .

Secondary or Recurrent Herpes Simplex Infection:

Reactivation of latent herpes simplex virus type 1 Triggers by

sunlight, stress, immunosuppression. Occur either at the site of

primary inoculation or in adjacent areas of surface epithelium

supplied by the involved ganglion. The most common site of

recurrence for HSV-1 is the vermilion border and adjacent skin of

the lips. This is known as herpes labialis (“cold sore” or “fever

blister”).

Clinical Features

Patients usually have prodromal symptoms of tingling, burning, or

pain in the site at which lesions will appear. Within a matter of

hours, the affected mucosa develops numerous pinhead vesicles,

which rapidly collapse to form numerous small, red lesions.

These lesions enlarge slightly and develop central ulceration

covered by yellow fibrin. Adjacent ulcerations may coalesce to

form larger, shallow, irregular ulcerations.

The gingiva is enlarged, painful, and extremely erythematous. In

addition, the affected gingiva often exhibits distinctive punched-

out erosions along the midfacial free gingival margins.

Histopathology

Microscopically, intraepithelial vesicles containing exudate,

inflammatory cells, and characteristic virus-infected epithelial

cells,which exhibit acantholysis, nuclear clearing, and nuclear

enlargement termed (ballooning degeneration). The acantholytic

epithelial cells may be referred to as Tzanck cell.

Nucleolar fragmentation occurs with a condensation of chromatin

around the periphery of the nucleus. Multinucleated epithelial cells

are formed by fusion between adjacent cells.

HSV1 cannot be differentiated from HSV2 histologically

.

Treatment of HSV1: After the systemic primary infection runs its

course of about 7 to 10 days, lesions heal without scar formation.

Acyclovir and analogs may control virus. Treatment must be

provided early to be effective.

Treatment of HSV2: Possible control with acyclovir and analogs

must be administered early. Systemic treatment much more

effective than topical treatment.

Varicella-Zoster (Chickenpox)

Primary varicella-zoster virus (VZV) infection in seronegative

individuals is known as varicella or chickenpox; secondary or

reactivated disease is known as herpes zoster.

Pathogenesis

Varicella is believed to be transmitted predominantly through the

inhalation of contaminated droplets. The condition is very

contagious and is known to spread readily from person to person.

Direct contact is an alternative way of acquiring the disease.

During the 2-week incubation period, virus proliferates within

macrophages, with subsequent viremia and dissemination to the

skin and other organs.

Clinical features

Because of widespread vaccination, varicella is uncommon today

in developed countries. Historically, a large majority of the

population experienced primary infection during childhood.

Fever, chills, malaise, headache and shortened disease course of

approximately 4 to 6 days may accompany a rash that involves

primarily the trunk and head and neck. The rash quickly develops

into a vesicular eruption that becomes pustular and eventually

ulcerates.

Perioral and oral manifestations are fairly common and may

precede the skin lesions. The vermilion border and palate are

involved most often, followed by the buccal mucosa. The gingival

lesions resemble those noted in primary HSV infection, but

distinguishing between the two is not difficult because the lesions

of varicella tend to be relatively painless.

Histopathological Features

The cytological alterations are virtually identical to those

described for HSV. The virus causes acantholysis, with formation

of numerous free-floating Tzanck cells, which exhibit nuclear

margination of chromatin and occasional multinucleation.

Treatment

For varicella in normal individuals, supportive therapy is generally

indicated. However, for immunocompromised patients, the

treatment includes systemically administered acyclovir,

vidarabine, and human leukocyte interferon. Corticosteroids

generally are contraindicated.

Hand-Foot-and-Mouth Disease

Etiology and Pathogenesis

HFM is a highly contagious viral infection that usually is caused

by Coxsackie type A16 or enterovirus 71, although other serologic

types of Coxsackie such as A5, A9, A10, B2, and B5 have been

isolated with the disease.

The virus is transferred from one individual to another through

airborne spread or fecal-oral contamination. With subsequent

viremia, the virus exhibits a predilection for mucous membranes

of the mouth and cutaneous regions of the hands and feet.

Clinical Features

This viral infection typically affects children younger than 5 years

of age. After a short incubation period, the condition resolves

spontaneously in 1 to 2 weeks.

Signs and symptoms are usually mild to moderate in intensity and

include low-grade fever, malaise, lymphadenopathy, and sore

mouth.

Oral lesions begin as vesicles that quickly rupture to become

ulcers that are covered by a yellow fibrinous membrane

surrounded by an erythematous halo. Lesions, which are multiple,

can occur anywhere in the mouth, although the palate, tongue, and

buccal mucosa are favored sites, while the lips and gingival are

usually spared.

Histopathology

The affected epithelium exhibits intracellular and intercellular

edema, which lead to the formation of an intraepithelial vesicle.

The vesicle enlarges and ruptures through the epithelial basal cell

layer, with formation of a subepithelial vesicle. Epithelial necrosis

and ulceration soon follow. Inclusion bodies and multinucleated

epithelial cells are absent.

Treatment

In most instances, enterovirus infections are self-limiting and

without significant complications. Therapy is directed toward

symptomatic relief; nonaspirin antipyretics and topical anesthetics,

such as dyclonine hydrochloride, often are beneficial.

Occasionally, certain strains produce infections with a more

aggressive clinical course. Body temperature above 102° F, fever

for longer than 3 days, severe vomiting, and lethargy have been

associated with increased risk for serious disease complications

and warrant close patient monitoring.

Herpangina

Etiology and Pathogenesis

Herpangina is an acute viral infection caused by another

Coxsackie type A virus (types A1-6, A8, A10, A22, B3, and

possibly others). It is transmitted by contaminated saliva and

occasionally through contaminated feces.

Clinical Features

Herpangina is usually more common in children than in adults.

Those infected generally complain of malaise, fever, dysphagia,

and sore throat after a short incubation period.

Intraorally, a vesicular eruption appears on the soft palate, faucial

pillars, and tonsils and persists for 4 to 6 days. A diffuse ery-

thematous pharyngitis is also present.

Signs and symptoms are usually mild to moderate and generally

last less than a week.

Treatment

Because herpangina is self-limiting, is mild and of short duration,

and causes few complications, treatment usually is not required.

Measles (Rubeola)

Etiology and Pathogenesis

Measles is a highly contagious viral infection caused by a member

of the paramyxo virus family. The virus, known simply as measles

virus, is an RNA-enveloped virus that is related structurally and

biologically to viruses of the orthomyxo virus family, which cause

mumps and influenza.

The virus is spread by airborne droplets through the respiratory

epithelium of the nasopharynx. The incubation period is between

10 and 11 days with a 1- to 7-day prodromal period.

Typically, an enanthem consists of early pinpoint elevations over

the soft palate that coalesces with ultimate involvement of the

pharynx with bright erythema; the tonsils may demonstrate bluish-

gray areas, so-called Herman spots.

Clinical Features

There are three stages of infection:

The first 3 days are dominated by the coryza (runny nose), cough,

and conjunctivitis (red, watery, and photophobic eyes). Fever

typically accompanies these symptoms. During this initial stage,

the most distinctive oral manifestation, Koplik spots, is seen.

These lesions represent foci of epithelial necrosis and appear as

numerous small, blue-white macules (or “grains of salt”)

surrounded by erythema. Typical sites of involvement include the

buccal and labial mucosa, and less often the soft palate.

The second stage begins, the fever continues, the Koplik spots

fade, and a maculopapular and erythematous rash begins. The face

is involved first, with eventual downward spread to the trunk and

extremities. Ultimately, a diffuse erythematous eruption is formed,

which tends to blanch on pressure.

In the third stage, the fever ends and the rash begins to fade, with

downward progression and replacement by brown pigmentation.

Ultimately, desquamation of the skin is noted in areas previously

affected by the rash.

Histopathology

Koplik spots represent areas of hyperparakeratotic epithelium with

spongiosis, dyskeratosis, and epithelial syncytial giant cells. The

number of nuclei within these giant cells ranges from 3 to more

than 25.

As the spot ages, the epithelium exhibits heavy neutrophilic

exocytosis leading to microabscess formation, epithelial necrosis,

and, ultimately, ulceration. Frequently, examination of the

epithelium adjacent to the ulceration reveals the suggestive

syncytial giant cells.

Treatment

The measles vaccine is a live, attenuated virus, which is included

in the widely used MMR (measles, mumps, and rubella) and

MMRV (measles, mumps, rubella, and varicella) vaccines.

No specific treatment for measles is known. Supportive therapy of

bed rest, fluids, adequate diet, and analgesics generally suffices.

IMMUNOLOGIC DISEASE

Pemphigus Vulgaris

Pemphigus is a group of autoimmune mucocutaneous diseases

characterized by intraepithelial blister formation. It results from a

breakdown or loss of intercellular adhesion, thus producing

epithelial cell separation known as acantholysis.

Four types of pemphigus are recognized: pemphigus vulgaris,

pemphigus foliaceus, pemphigus erythematosus, and pemphigus

vegetans.

Etiology and Pathogenesis

All forms of the disease share a common autoimmune etiology;

circulating auto-antibodies are responsible for the earliest

morphologic event, the dissolution or disruption of intercellular

junctions and loss of cell-to-cell adhesion. The ease and extent of

epithelial cell separation are generally directly proportional to the

titer of circulating pemphigus antibody.

Clinical Features

The average age at diagnosis is 50 years, although rare cases may

be seen in childhood. The lesions present as painful ragged

erosions and ulcers proceeded by bullae. The first signs of the

disease appear in the oral mucosa in approximately 60% of cases.

Such lesions may precede the onset of cutaneous lesions by

periods of up to 1 year.

The skin lesions appear as flaccid vesicles and bullae, which

rupture quickly, usually within hours to a few days, leaving an

erythematous, denuded surface, red, painful, ulcerated base. Ulcers

range in appearance from small aphthous-like lesions to large

maplike lesions.

Gentle traction on clinically unaffected mucosa may produce

stripping of epithelium, a positive Nikolsky’s sign.

Histopathology

Biopsy specimens of perilesional tissue show characteristic

intraepithelial separation, which occurs just above the basal cell

layer of the epithelium. Sometimes the entire superficial layers of

the epithelium are stripped away, leaving only the basal cells, The

cells of the spinous layer of the surface epithelium typically appear

to fall apart, a feature that has been termed acantholysis, and the

loose cells tend to assume a rounded shape.

Treatment and Prognosis

The high morbidity and mortality rates previously associated with

pemphigus vulgaris have been reduced radically since the

introduction of systemic corticosteroids.

For more severely affected patients, a high-dose systemic

corticosteroid regimen plus other nonsteroidal immunosuppressive

agents with or without plasmapheresis may be necessary.

Topical Steroids

Topical corticosteroids may be used intraorally as an adjunct to

systemic therapy, with a possible concomitant lower dose of

systemic corticosteroid.

Mucous Membrane Pemphigoid

A group of chronic, blistering, mucocutaneous autoimmune

diseases in which tissue-bound autoantibodies are directed against

one or more components of the basement membrane. It is referred

to clinically as gingivosis or desquamative gingivitis.

Etiology and Pathogenesis

MMP is an autoimmune process with an unknown stimulus.

Deposits of immunoglobulin's and complement components along

the basement zone are characteristic.

Clinical Features

This is a disease of adults and the elderly and tends to affect

women more than men, and rarely reported in children.

Oral mucosal lesions typically present as superficial ulcers,

sometimes limited to attach gingival.

Bullae are not commonly seen because the blisters are fragile

and short lived.

Lesions are chronic and persistent and may heal with a scar.

Risks include scarring of the canthus (symblepharon), inversion

of the eyelashes (entropion), and resultant trauma to the cornea

(trichiasis).

Gingival lesions often present as bright red patches or confluent

ulcers extending to unattached gingival mucosa with mild to

moderate discomfort.

With chronic form, the pain associated with oral MMP typically

diminishes in intensity.

Histopathological feature

Biopsy of perilesional mucosa shows a split between the surface

epithelium and the underlying connective tissue in the region of

the basement membrane. A mild chronic inflammatory cell

infiltrate is present in the superficial submucosa.

Direct immunofluorescence studies of perilesional mucosa show a

continuous linear band of immunoreactants at the basement

membrane zone in nearly 90% of affected patients.

Treatment and Prognosis

The patient should be referred to an ophthalmologist who is

familiar with the ocular lesions.

Corticosteroids are typically used to control MMP.

Prednisone is used for moderate to severe disease, and topical

steroids for mild disease and maintenance.

In addition, if the patient is experiencing symptoms at other

anatomic sites, then the appropriate specialist should be

consulted.

Dermatitis Herpetiformis

Etiology and Pathogenesis

Dermatitis herpetiformis is a cutaneous vesiculobullous disease

characterized by intense pruritus. The disease is associated with

granular IgA deposits in the papillary dermis that precipitate with

an epidermal transglutaminase, an enzyme not normally present in

the papillary region of normal skin.

Dermatitis herpetiformis is frequently associated with the gluten-

sensitive enteropathy, celiac disease.

Clinical Features

Chronic disease typically seen in young and middle-aged adults,

with a slight male predilection.

Cutaneous lesions are papular, erythematous, vesicular, and

often intensely pruritic.

Lesions are usually symmetric in their distribution over the

extensor surfaces, especially the elbows, shoulders, sacrum, and

buttocks.

In the oral cavity, dermatitis herpetiformis is uncommon, with

vesicles and bullae that rupture, leaving superficial nonspecific

ulcers with a fibrinous base with erythematous margins.

Lesions may involve both keratinized and nonkeratinized

mucosa, and may be seen in a significant number of those with

this disease.

Histopathology

Collections of neutrophils, eosinophils, and fibrin are seen at the

papillary tips of the dermis. Subsequent exudation at this location

contributes to epidermal separation. A lymphophagocytic infiltrate

is seen in perivascular spaces.

Treatment and Prognosis

1. Dermatitis herpetiformis generally is treated with dapsone,

sulfoxone, and sulfapyridine.

2. Gluten -free diet may also be part of the therapeutic regimen

3. Dermatitis herpetiformis is a lifelong condition, often exhibiting

long periods of remission. Many patients, however, may be

relegated to long-term dietary restrictions or drug treatment or

both.

HEREDITARY DISEASE

Epidermolysis Bullosa

Etiology and Pathogenesis

Epidermolysis bullosa is a hereditary variety of diseases that

basically are characterized by the formation of blisters at sites of

minor trauma. The acquired nonhereditary autoimmune form,

known as epidermolysis bullosa acquisita, is unrelated to the

other types and often is precipitated by exposure to specific drugs.

In the hereditary forms of epidermolysis bullosa, circulating

antibodies are not evident. Rather, pathogenesis appears to be

related to genetic defects in basal cells, hemidesmosomes, or

anchoring connective tissue filaments, depending on the disease

subtype.

Clinical Features

The initial lesions are vesicles or bullae, which are seen early in

childhood and develop on areas exposed to low-grade, chronic

trauma, such as the knuckles or knees. The bullae may be

widespread, severe and rupture, resulting in erosions or ulcerations

that ultimately heal with scarring. In the process, appendages such

as fingernails may be dystrophic in some forms of this disease.

The oral manifestations are typically mild, with some gingival

erythema and tenderness. Gingival recession and reduction in the

depth of the buccal vestibule dystrophic in some forms of this

disease.

Oral lesion includes bullae that heal with scar formation, a

constricted oral orifice resulting from scar contracture, and

hypoplastic teeth. These changes are most pronounced in the type

known as recessive dystrophic epidermolysis bullosa.

Histopathological Feature

Electron microscopic examination reveals clefting at the level

below the lamina densa of the basement membrane in the

dystrophic forms.

Treatment and Prognosis

Management of the oral manifestations for patients who are

susceptible to mucosal bulla formation:

Topical 1% neutral sodium fluoride solution should be

administered daily to prevent dental caries.

A soft diet that is as noncariogenic as possible, as well as

atraumatic oral hygiene procedures, should be encouraged.

Maintaining adequate nutrition for affected patients is critical to

ensure optimal wound healing.

Endosseous dental implants, followed by fixed dental

prostheses, have been successfully placed in some patients with

recessive dystrophic epidermolysis bullosa.

If dental restorative care is required, the lips should be

lubricated to minimize trauma.

Injections for local anesthesia can usually be accomplished by

depositing the anesthetic slowly and deeply within the tissues.

For extensive dental care, endotracheal anesthesia may be

performed without significant problems in most cases.