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Craig B.

Fowler, Col, USAF, DC


6 Feb 2004

MUCOCUTANEOUS LESIONS
(VESICULOBULLOUS AND ULCERATIVE DISEASES
OF THE ORAL CAVITY)

I. INTRODUCTION

A. Vesiculoerosive diseases present a significant problem in accurate


diagnosis for the clinician because the clinical appearance and
clinical course of many of these lesions are very similar.

B. In order to obtain the correct diagnosis, an accurate assessment of


the morphology and distribution of the lesions as well as the past
history of any similar lesions is an essential first step.

C. Baseline laboratory studies may also be helpful in diagnosis and


later in the management of many of these diseases.

D. Although a few of these diseases may be accurately diagnosed on


clinical grounds alone, most will require tissue biopsy for
definitive diagnosis.

E. Immunofluorescence is an adjunctive test to the usual biopsy and is


used in a number of these diseases to confirm the diagnosis or to
assess disease activity.

II. IMPORTANT CLINICAL PARAMETERS

A. Location
1. Bound or unbound mucosa or both
2. Extraoral lesions

B. Morphology
1. Size of ulcer or blister - less than or more than 0.5 cm
2. Outline - round/oval or irregular, raised or flat border
3. Depth - superficial or deep
4. Solitary or multiple
5. Separate or coalescing

C. History
1. Onset - slow or rapid
2. Duration - self-limiting or persistent
3. Age of patient

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Craig B. Fowler, Col, USAF, DC
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III. RECURRENT APHTHOUS ULCERATION (RAU)

- a disease of unknown etiology characterized by solitary or multiple


recurring painful oral ulcers
- 10-20% of population affected
- possible causes: genetic, nutritional, hormonal, allergic,
psychological (stress), traumatic, infectious (H. pylori?), autoimmune
- primarily a T-cell mediated response with cell lysis occurring in all
epithelial cell layers

A. Minor RAU (Canker sore)

- superficial ulcer(s) with yellow-white center and red halo


- moderate pain
- located on movable mucosa
- 0.2-1.0 cm diameter
- persist for 7-14 days
- heal without scarring

B. Major RAU (Sutton's Disease, Periadenitis Mucosa Necrotica


Recurrens - PMNR)

- deep ulcers >1.0 cm diameter


- severe pain
- located on movable mucosa (soft palate, tonsillar folds are common
sites)
- persist up to 6 weeks
- heal with scarring

C. Herpetiform Ulceration

- rare variant of RAU


- crops of multiple small (1mm) ulcers on erythematous base
- moderate-to-severe pain
- any oral site (primarily movable mucosa)
- may be present almost continuously with short remissions

D. Treatment of RAU

- R/O underlying cause, such as anemia, systemic disease, etc.


- minor RAU - chlorhexidine (Peridex, Perioguard), topical steroids,
hydroxypropylcellulose (Zilactin), CO2 laser, ultrasound, amlexanox,
silver nitrate (Negatan), Debacterol, Sucralfate,and many other “home
remedies”
- major RAU – intralesional (preferred) or systemic steroids
- herpetiform ulceration - same as minor RAU, tetracycline rinses

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Craig B. Fowler, Col, USAF, DC
6 Feb 2004

IV. SYSTEMIC DISEASES CAUSING RAU-LIKE ORAL LESIONS

A. Behcet's Syndrome

- probable autoimmune etiology


- classic symptom triad: oral ulcers, genital ulcers, and ocular
inflammation
1. oral ulcers - resembling minor or major RAU
2. genital ulcers - scrotum, labia majora
3. ocular lesions - conjunctivitis, uveitis
- skin lesions: - papulopustular lesions - trunk, limbs, genitalia,
erythema nodosum
- systemic: - arthralgia, thrombophlebitis, CNS, cardiac, pulmonary
involvement

B. Crohn's Disease (Regional Enteritis)

- granulomatous inflammation of unknown etiology


- usually affects terminal ileum and colon
- perianal fistulae or abscesses
- peak ages: 12-30 years, 50 years
- fever, mild diarrhea, pain, weight loss, weakness
- oral: papillary projections/pustules on erythematous base
(pyostomatitis vegetans)
- "cobblestone" appearance to buccal mucosa
- oral ulcers resembling RAU
- increased risk of bowel carcinoma

C. Ulcerative Colitis

- usually affects sigmoid colon and rectum


- peak age: 15-30 years, 50-65 years
- bloody diarrhea, pain, cramps, fever, weight loss
- oral ulcers resembling RAU
- pyostomatitis vegetans
- increased risk of colon carcinoma, especially in long-standing
extensive disease

D. Others - Agranulocytosis, cyclic neutropenia, celiac disease, iron-


deficiency anemia, HIV infection, chemotherapy

E. PFAPA Syndrome
- Periodic Fever, Aphthous stomatitis, Pharyngitis, Adenitis
- symptom complex of unknown etiology affecting primarily young children,
but may last into later childhood
- age of onset is typically prior to 5 years old
- periodic (monthly) episodes of high fever (up to 1040) lasting for 4-5
days with intervening symptom-free periods
- not associated with long-term sequelae, generally subsides or completely
resolves with time
- tx: cimetidine (Tagamet), corticosteroids, tonsillectomy & adenoidectomy

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V. HERPES SIMPLEX VIRAL INFECTION (HSV)

- very common viral acute infectious disease


- two immunologic types: HSV-1 and HSV-2
HSV-1: face, lips, oral cavity, upper body skin
HSV-2: genitals, lower body skin
- two kinds of infection: primary and recurrent

A. Primary Herpes

- first response to virus, many cases are subclinical


- “primary herpetic gingivostomatitis”
- fever, cervical lymphadenopathy
- painful erythematous gingiva, lips, tongue, buccal mucosa,
palate, pharynx, and tonsils
- crops of small (1mm) painful vesicles/ulcers, some of which
may coalesce into larger ulcers with scalloped borders
- self limiting with resolution in 7-14 days
- virus remains dormant in ganglia or along nerve trunk

B. Recurrent Herpes

- subsequent reactivation of virus: trauma, UV light, fever, etc.


- virus creeps down sensory nerves and exits on skin or
mucosal surface
- crops of small (1mm) vesicles/ulcers
- intraorally seen only on bound mucosa
- resolution in 7-10 days

C. Diagnosis: - confirmed by exfoliative cytology smear or culture;


viral cytopathogenic effect seen in epithelial cell nuclei (smear)

D. Treatment: - primary HSV: Acyclovir (Zovirax); recurrent HSV: topical


anesthetics, ice, penciclovir (Denavir), docosanol (Abreva)

VI. HERPES ZOSTER (Shingles)

- caused by reactivation of varicella zoster virus (VZV)


- primary infection with VZV causes chickenpox
- reactivation may occur for no apparent reason or secondary to
trauma, malignancy (esp. lymphoma), or immunosuppression
- oral: unilateral vesicles/ulcers in distribution of trigeminal
nerve
- Hunts' Syndrome: - VZV infection of geniculate ganglion; facial
paralysis, pain, and vesicles in external ear and oral cavity,
hoarseness, tinnitis, vertigo
- treatment: Acyclovir (Zovirax)
- complication: post-herpetic neuralgia

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VII. ERYTHEMA MULTIFORME (EM)

- acute mucocutaneous disease of unknown etiology


- hypersensitivity response
- may be triggered by HSV infection, medications, vaccination,
radiation therapy, other diseases
- affects young adults most often
- rapid onset (1-2 days) of erythematous maculopapular/
vesiculobullous eruption on skin of trunk, extremities,
and face in symmetric distribution
- target lesions on skin (esp. palms and soles)
- oral: painful irregular ulcerations in any location,
crusting of lips
- treatment: self limiting disease - requires supportive/
symptomatic tx; systemic steroids for more severe cases
- Stevens-Johnson Syndrome - severe form of EM involving
ocular, oral, and genital areas, often preceded by prodrome of fever,
malaise, headache, sore throat, rhinitis, cough, and arthralgia
(more often triggered by drugs than EM)
- Toxic Epidermal Necrolysis (Lyell's Disease) - very
severe form of EM involving large confluent areas of
skin, often fatal

VIII. PEMPHIGUS

- autoimmune disease affecting skin and mucosal surfaces


- autoantibodies directed against components of the desmosomes –
desmoglein I (p. foliaceous), desmoglein III (p. vulgaris) – do not
require complement activation to produce acantholysis
- oral involvement may precede skin involvement
- + Nikolsky sign: lateral pressure on uninvolved skin or
mucosa will cause new lesion
- 2 main types:
1. Pemphigus vulgaris - causes flaccid bullae on skin
- most common type in oral cavity
2. Pemphigus foliaceous - exfoliative dermatitis, no oral lesions
- oral: painful ragged, red ulcers or collapsed bullae
- histo: suprabasilar separation, or cleft, with acantholytic (Tzanck)
cells
- Immunofluorescence (IF): direct and indirect IF usually
positive in intercellular spaces for IgG, C3
- treatment: systemic steroids alone or incombination with
steroid-sparing drugs such as cyclophosphamide, azathioprine,
or cyclosporine. Alternative therapy with gold, dapsone,
hydroxychloroquine, and nicotinamide with tetracycline has also
been employed with some success. Plasmapharesis or pulse IV steroids
may be used for rapid control of severe or refractory cases.
Intralesional steroids may be used either alone for control of
localized mild disease, or in combination with systemic medications
for recalcitrant individual lesions or mild flares in disease
activity

- Paraneoplastic Pemphigus - severe mucocutaneous eruption

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Craig B. Fowler, Col, USAF, DC
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seen in patients with an underlying malignancy (usually


non-Hodgkin's lymphoma). Clinical features are suggestive
of erythema multiforme with lip and ocular involvement commonly seen.
Bronchiolar respiratory epithelium may also be affected. Histologic
features include acantholysis, keratinocyte necrosis, and vacuolar
interface change. Direct and indirect IF shows deposition of IgG
and
complement in the intercellular spaces of epithelial cells as well
as
granular-linear deposition of complement in the basement membrane
zone. Indirect IF is best demonstrated with rat urinary bladder as
the substrate. Five possible autoantigens have been isolated
including desmoplakin I (250kD), desmoplakin II (210kD), and BP
antigen (230kD). Treatment is with systemic steroids-cyclosporine
combinations and is generally refractory and often fatal.

IX. PEMPHIGOID

- as the name implies, it resembles pemphigus


- autoimmune disease in which patients produce autoantibodies to a
component or components of the basement membrane zone (BMZ)
- two main types:
1. Bullous Pemphigoid (BP) - seen mainly on skin, causing
tense
bullae. Autoantigens are BP Antigen I (230kd) and BP Antigen II
(180kd) which are major components of the hemidesmosome.
2. Mucous Membrane Pemphigoid-MMP- involves primarily mucous
membranes - oral, respiratory, ocular, and genital. Several
possible autoantigens isolated including epiligrin (laminin 5),
BP antigen II (180kD), B-4 integrin and others; these antigens
are located primarily in the the lamina lucida (see diagram).
- evidence now suggests that that there are many subtypes of MMP based
on
the specific autoantigen involved (Chan L, et al)
- to date, 10 different BMZ target antigens have been recognized by the
autoantibodies in patients with MMP
- ocular: seen in 10-20% of cases; entropion, trichiasis, adhesions and
scarring of conjunctiva (symblepharon, ankyloblepharon) which may
result in blindness; more likely to have ocular involvement if both IgA
and IgG antibodies are involved (Chan L, et al, Setterfield J, et al)
- oral: painful erosive lesions, esp. common on gingiva
- histo: subepithelial separation at basement membrane with
variable inflammation
- IF: direct IF positive along basement membrane in smooth
linear pattern for IgG, C3, and/or IgA. Indirect IF usually
negative since circulating autoantibodies are uncommon
- indirect IF on salt-split skin may show immunoreactants located on
either the epidermal side (roof) or the dermal side (floor) of the
blister
- treatment: - topical or systemic steroids, dapsone
- referral to ophthalmologist is mandatory for MMP to r/o ocular
involvement
- anti-epiligin MMP is more serious form of disease with circulating

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autoantibodies more commonly found; also associated with an increased


risk of solid cancer (adenocarcinoma) and in less chance of remission
in one study (Egan C, et al)

X. EPIDERMOLYSIS BULLOSA ACQUISITA (EBA)

- not hereditary as in other forms of epidermolysis bullosa


- autoantibodies directed against type VII collagen (290kD), the major
component of anchoring fibrils
- characterized by trauma-induced blisters located primarily on acral
skin which typically heal with scarring, milia, and nail dystrophy
- mucous membrane involvement is common and may include oral, ocular,
genital, laryngeal, and esophageal mucosa
- the clinical spectrum of this disease is still evolving and there is
overlap with other autoimmune blistering diseases such as MMP
- if lesions are primarily on mucosa, recent consensus is that this form
of EBA is more properly considered a subtype of MMP (Chan, et al)
- histo: subepithelial separation similar to BP; direct IF also similar
to BP; direct or indirect IF on salt-split skin may be helpful in
distinguishing EBA from BP or MMP, but not bullous SLE - separation
from bullous SLE must be based on serologic studies (ANA’s, etc.)
- IF: direct IF identical to MMP, indirect IF on salt-split skin shows
immunoreactants on dermal side (floor) of blister
- tx: systemic prednisone in combination with other immunosuppressive
agents such as azathioprine, cyclophosphamide, and cyclosporine

XII. DERMATITIS HERPETIFORMIS (DH)

- symmetric eruption of grouped papulovesicular or pustular lesions


located predominantly on elbows, knees, buttocks, and scalp
- skin lesions are very pruritic
- oral vesicles and bullae may be seen
- virtually all patients have a subclinical or clinical gluten-senstive
enteropathy (similar to celiac disease)
- histo: subepithelial separation with neutrophils in the connective
tissue papillae; direct IF shows granular deposits of IgA at the
basement membrane zone concentrated in the connective tissue papillae
- tx: dapsone, sulfapyridine, gluten-free diet

XIII. LINEAR IgA DISEASE & CHRONIC BULLOUS DISEASE OF CHILDHOOD

- similar to DH except IgA is deposited in smooth linear pattern at BMZ


- autoantibodies to 97 kD and 120 kD proteins in lamina lucida
- not usually associated with gluten-senstive enteropathy
- skin-based lesions are symmetrically distributed annular plaques with
peripheral blisters resembling a “cluster of jewels”
- mucosal involvement is more frequent than in DH: 65% have oral lesions
- if lesions are primarily on mucosa, recent consensus is that this form
of linear IgA disease is more properly considered a subtype of MMP
(Chan, et al)
- conjunctival scarring in 40% (higher than in MMP)

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- if only mucosal involvement, may actually best be considered a subtype


of MMP (see consensus paper by Chan, et al)
- tx: dapsone, sulfapyridine, systemic steroids

XIV. LICHEN PLANUS

- lichen Planus (LP) is a very common dermatologic disease of unknown


etiology which commonly involves the oral cavity
- mediated by T-lymphocytes (CD4, CD8) perhaps activated by antigen-
presenting dendritic cells in the overlying epithelium
- although some European and Asian studies have linked LP with hepatitis C
infection, this does not seem to be true in the US at this time (Eisen)
- skin: - purple, polygonal, pruritic papules with Wickham's striae;
symmetric distribution on wrists, forearms, knees, thighs, shins and
trunk (esp. sacrum)
- remitting, relapsing course
- Koebner phenomenon - new lesions may be created by scratching or other
trauma in area of pre-existing lesions
- oral: - most common on buccal mucosa, tongue, and gingiva;
reticular, erosive, hypertrophic (plaque), atrophic, bullous, and
papular types
- vulvovaginal-gingival syndrome of LP: synchronous or metachronous
presentation of oral and genital erosive lesions; genital lesions are
more refractory to treatment; may require systemic steroids
- various medications may induce or exacerbate LP (LP-like drug
reaction),
and various metallic dental restorative materials (especially
amalgam)may also be associated with localized lichenoid mucosal
reactions (Thornhill M, et al)
- histo: hyperkeratosis, subepithelial dense, band-like lymphocytic
infiltrate, liquefactive degeneration of basal layer, cytoid bodies
- IF: direct IF positive for fibrin at basement membrane zone in shaggy
linear pattern, cytoid bodies frequently positive for IgG or IgM
- treatment: topical steroids (Lidex, Temovate, Ultravate), tacrolimus
- follow-up: long-term recommended - slightly increased risk of
development of oral SCCA in patients with long-standing erosive LP
(Eisen, Silverman, Epstein)

XV. CHRONIC ULCERATIVE STOMATITIS

- chronic or recurrent oral ulcerative lesions associated with


stratified epithelium-specific antinuclear antibodies (SES-ANA)
- autoantigen recently characterized as 70 kd epithelial nuclear protein
and thought to a member of the p53 tumor suppressor gene family
- most cases in females; age range 35-71 years (most in 43-57 age range)
- clinical features may mimic erosive lichen planus or desquamative
gingivitis
- all patients have oral lesions; skin lesions have also been documented
in a few patients
- histo: lichenoid infiltrate with fibrin deposition
- presence of speckled nuclear staining for SES-ANA on both direct and
indirect IF is key to diagnosis:

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- direct IF: normal skin or oral mucosa


- indirect IF: using guinea pig esophagus as substrate
- all other ANA’s are negative
- tx: hydroxychloroquine (Plaquenil) has been most effective;
clobetasol propionate (Temovate) and fluocinonide (Lidex) have also
been used with some success

XVI. LUPUS ERYTHEMATOSUS (LE)

LE is an autoimmune disease with a spectrum of clinical


presentations. At the ends of the spectrum, two main types exist:
discoid LE and systemic LE. All subtypes are more common in females
than males.

Discoid Lupus Erythematosus (DLE)

- disease limited to skin


- usually no serologic abnormalities
- lesions are well-defined erythematous "discoid" patches with
adherent
scales and follicular plugging; scarring is seen in old lesions
- lesions are commonly seen on nose and malar areas; scalp, ears, oral
mucosa, and vermilion of lip

Systemic Lupus Erythematosus (SLE)

- multisystem disease characterized by cutaneous lesions and systemic


involvement; arthritis and renal involvement are most common
- diagnosis can be made if 4 or more of the following criteria are
present serially or simultaneously: malar rash, discoid rash,
photosensitivity, oral ulcers, arthritis, serositis, renal disorder,
neurologic disorder, hematologic disorder, immunologic disorder,
antinuclear antibodies (ANA)
- ANA's are primarily directed against double-stranded DNA
- rare bullous form of SLE has recently been described with clinical
and IF findings overlapping with those of bullous pemphigoid,
dermatitis herpetiformis, erythema multiforme, and epidermolysis
bullosa acquisita
- 50% of patients with SLE have heart valve damage. 1-4% of these
patients develop bacterial endocarditis (Liebmann-Sachs
endocarditis)
which necessitates antibiotic coverage for patients undergoing
dental
procedures associated with transient bacteremias

Intermediate forms of LE:

Disseminated DLE

- multiple discoid lesions on head, trunk, arms


- SLE may subsequently develop in some of these patients

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Subacute Cutaneous Lupus Erythematosus (SCLE)

- extensive erythematous non-scarring lesions on face, neck, upper


trunk, extensor surfaces of arms, dorsa of hands and fingers with
severe photosensitivity
- lesions are often annular or polycyclic
- associated with antibodies to Ro (SS-A) and La (SS-B) antigens
- mild systemic involvement: fever, malaise, arthralgia, myalgia
General Comments - Lupus Erythematosus

- The oral lesions of LE are similar to erosive lichen planus


clinically, and there is also some overlap histologically.
- Direct immunofluorescence of uninvolved skin (Lupus Band Test) is
helpful in distinguishing LE from other bullous diseases and in
distinguishing SLE from DLE.
- Oral findings need to be correlated with skin lesions, systemic
manifestations, and serum laboratory evaluations for proper
diagnosis.

XVII. CINNAMON REACTION

- oral mucosal hypersensitivity reaction to cinnamon-flavoring agents


- toothpastes, candies, mints, chewing gum, mouthrinses, and even
cinnamon toast may be the allergen
- lesions may mimic leukoplakia, lichen planus, or erosive lichen planus
clinically
- histo: lichenoid inflammatory infiltrate with perivascular component
and variable formation of lymphoid aggregates; in some cases looks
similar to lupus erythematosus; some lesions may exhibit a pattern
mimicking psoriasis
- clinical resolution occurs after identification and withdrawal of
offending agent

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Craig B. Fowler, Col, USAF, DC
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IMMUNOFLUORESCENCE (IF)

1. Direct IF - test performed on patient's tissue in order to identify


tissue-bound autoantibodies
a. This test cannot be performed on formalin-fixed tissue.
b. The tissue must be frozen at the time of biopsy or placed in a
special
carrying medium such as Michel's solution before transporting to lab.
c. The tissue is then specially processed and observed under a
fluorescence microscope.
d. The location and pattern of fluorescence is important in determining
the diagnosis.

2. Indirect IF - test done on patient's serum in order to identify


circulating autoantibodies
a. This test is especially helpful in the diagnosis of pemphigus, in
measuring disease activity, and in monitoring the progress of
treatment.

Direct IF Indirect IF

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Craig B. Fowler, Col, USAF, DC
6 Feb 2004

SAMPLE PRESCRIPTIONS

Rx: Temovate (Clobetasol propionate) ointment, 0.05 %


Disp: 1 tube (15, 30, 45, or 60 gram)
Sig: Apply to affected areas b.i.d and rub in gently
and completely

Rx: Lidex (fluocinonide) ointment, 0.05 %


Disp: 1 tube (15, 30, 60, or 120 gram)
Sig: Apply to affected areas 2 – 4 times/day and rub in
gently and completely

Rx: Diprolene (betamethasone dipropionate) gel, 0.05 %


Disp: 1 tube (15 or 45 gram)
Sig: Apply to affected areas b.i.d. and rub in gently and
completely

Rx: Mycelex (clotrimazole) troches


Disp: 70 troches
Sig: Take 1 troche 5 times/day x 14 days

1-2-3 Mouthrinse
Rx: Aphthasol (amlexanox) oral paste, 5 % Rx: Dimetapp elixir 40 ml
Disp: 1 tube (5 gram) Dist H2O 80 ml Mix
Sig: Apply to affected areas q.i.d. following Kaopectate 120 ml
oral hygiene after meals and at bedtime Disp: 1 bottle
Sig: Rinse orally p.r.n.

Rx: Aristocort syrup


Benedryl Elixir mix in equal parts
Disp: 1 bottle
Sig: Rinse 1 T orally and expectorate q.i.d.
(keep refrigerated for longer shelf life)

Rx: Peridex (chlorhexidine gluconate), 0.12 % Rx: Periogard, 0.12 %


Disp: 1 dispenser pack (3 1-pint bottles) Disp: 1 bottle (16 oz)
Sig: Rinse 15 ml orally for 30 sec, b.i.d. morning Sig: Rinse ½ oz
and evening after toothbrushing

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VESICULOEROSIVE DISEASES - GENERAL

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6 Feb 2004

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