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intensive medical care, some patients die as a result of infectious complications.The “mitten” deformity of the hands, seen in recessive dystrophic epidermolysis bullosa, can be corrected with
plastic surgery, but the problem usually recurs after a period of time, and surgical intervention is required every 2
years on average. With esophageal involvement, dysphagia may be a significant problem, resulting in malnutrition
and weight loss. Placement of a gastrostomy tube may be necessary at times. Patients with the recessive dystrophicforms are also predisposed to development of cutaneous squamous cell carcinoma. This malignancy often develops
in areas of chronic ulceration during the second through third decades of life and represents a significant cause of
death for these patients. Infrequently, the lingual mucosa of affected patients has been reported to undergo
malignant transformation as well.
Management of the oral manifestations also depends on the type of the disease. For patients who are susceptible to
mucosal bulla formation, dental manipulation should be kept to a minimum. To achieve this, 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. Forextensive dental care, endotracheal anesthesia may be performed without significant problems in most cases.
Unfortunately, because of the genetic nature of these diseases, no cure exists. Genetic counseling of affected
families is indicated. Both prenatal diagnosis and preimplantation diagnosis are available as adjuncts to family
planning.
Immune-Mediated Diseases and Their Evaluation
Several conditions discussed in this chapter are the result of inappropriate production of antibodies by the patient
(autoantibodies). These autoantibodies are directed against various constituents of the molecular apparatus that hold
epithelial cells together or that bind the surface epithelium to the underlying connective tissue. The ensuing damage
produced by the interaction of these autoantibodies with the host tissue is seen clinically as a disease process, often
termed an immunobullous disease. Because each disease is characterized by production of specific types ofautoantibodies, identification of the antibodies and the tissues against which they are targeted is important
diagnostically. The two techniques that are widely used to investigate the immunobullous diseases are 1) direct
immunofluorescence and 2) indirect immunofluorescence studies. Following is a brief overview of how they work.
Direct immunofluorescence is used to detect autoantibodies that are bound to the patientʹs tissue. Before testing
can take place, several procedures must occur. Inoculating human immunoglobulins into a goat creates antibodies
directed against these human immunoglobulins. The antibodies raised in response to the human immunoglobulins
are harvested from the animal and tagged with fluorescein, a dye that glows when viewed with UV light. As
illustrated on the left side of Fig. 16‑47 , a frozen section of the patientʹs tissue is placed on a slide, and this is
incubated with fluorescein‑conjugated goat antihuman antibodies. These antibodies bind to the tissue at any site
where human immunoglobulin is present. The excess antibody suspension is washed off, and the section is then
viewed with a microscope having a UV light source.
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FIG. 16-47 Immunofluorescence Techniques. Comparison of the techniques for direct and indirect immunofluorescence . The left
side depicts the direct immunofluorescent findings in cicatricial pemphigoid, a disease that has autoantibodies directed toward thebasement zone. The right side shows the indirect immunofluorescent findings for pemphigus vulgaris, a disease that hasautoantibodies directed toward the intercellular areas between the spinous cells of the epithelium. Ig, Immunoglobulin; UV,ultraviolet.
With indirect immunofluorescence studies, the patient is being evaluated for presence of antibodies that are
circulating in the blood. As shown on the right side of Fig. 16‑47 , a frozen section of tissue that is similar to humanoral mucosa (e.g., Old World monkey esophagus) is placed on a slide and incubated with the patientʹs serum. If there
are autoantibodies directed against epithelial attachment structures in the patientʹs serum, then they will attach to
the homologous structures on the monkey esophagus. The excess serum is washed off, and fluorescein‑conjugated
goat antihuman antibody is incubated with the section. The excess is washed off, and the section is examined with
UV light to detect the presence of autoantibodies that might have been in the serum.
Examples of the molecular sites of attack of the autoantibodies are seen diagrammatically in Fig. 16‑48. Each site is
distinctive for a particular disease; however, the complexities of the epithelial attachment mechanisms are still being
elucidated, and more precise mapping may be possible in the future. A summary of the clinical, microscopic, and
immunopathologic features of the more important immune‑mediated mucocutaneous diseases is found in Table 16‑
3.
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FIG. 16-48 Epithelial Attachment Apparatus. Schematic diagram demonstrating targeted structures in several immune-mediated
diseases. BMZ, Basement membrane zone.
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TABLE 16-3
Chronic Vesiculoulcerative Diseases
Condition Mean Age Sex
Predilection
Clinical
Features
Histopathologic
Features
Direct
Immunofluorescence
Indirect
Immunofluorescence
Pemphigus
vulgaris
Fourth to
sixth
decade
Equal Vesicles,
erosions,
and
ulcerationson any
oral
mucosal or
skin
surface
Intraepithelial
clefting
Positive intercellular Positive
Paraneoplastic
pemphigus
Sixth to
seventh
decade
Equal Vesicles,
erosions,
and
ulcerations
on any
mucosal or
skin
surface
Subepithelial and
intraepithelial
clefting
Positive, intercellular
and basement
membrane zone
Positive (rat bladder)
Mucous
membrane
pemphigoid
Sixth to
seventh
decade
Female Primarily
mucosal
lesions
Subepithelial
clefting
Positive, basement
membrane zone
Negative
Bullous
pemphigoid
Seventh to
eighth
decade
Equal Primarily skin
lesions
Subepithelial
clefting
Positive, basement
membrane zone
Positive
Erythema
multiforme
Third to
fourth
decade
Male Skin and
mucosa
involved;
target
lesions on
skin
Subepithelial
edema and
perivascular
inflammations
Nondiagnostic Negative
Lichen planus Fifth to
sixth
decade
Female Oral and/or
skin
lesions;
may or
may not
be erosive
Hyperkeratosis,
saw‑toothed
rete ridges,
bandlike
infiltrate of
lymphocytes
Fibrinogen, basement
membrane zone
Negative
◆ Pemphigus
The condition known as pemphigus represents four related diseases of an autoimmune origin:
1. Pemphigus vulgaris2. Pemphigus vegetans
3. Pemphigus erythematosus
4. Pemphigus foliaceus
Only the first two of these affect the oral mucosa, and the discussion is limited to pemphigus vulgaris. Pemphigus
vegetans is rare; most authorities now feel it represents simply a variant of pemphigus vulgaris.
Pemphigus vulgaris is the most common of these disorders (vulgaris is Latin for common). Even so, it is not seen
very often. The estimated incidence is one to five cases per million people diagnosed each year in the general
population. Nevertheless, pemphigus vulgaris is an important condition because, if untreated, it often results in the
patientʹs death. Furthermore, the oral lesions are often the first sign of the disease, and they are the most difficult to
resolve with therapy. This has prompted the description of the oral lesions as “the first to show, and the last to go.”
The blistering that typifies this disease is due to an abnormal production, for unknown reasons, of autoantibodies
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that are directed against the epidermal cell surface glycoproteins, desmoglein 3 and desmoglein 1. These
desmogleins are components of desmosomes (structures that bond epithelial cells to each other), and the
autoantibodies attach to these desmosomal components, effectively inhibiting the molecular interaction that is
responsible for adherence. As a result of this immunologic attack on the desmosomes, a split develops within the
epithelium, causing a blister to form. Desmoglein 3 is preferentially expressed in the parabasal region of the
epidermis and oral epithelium, whereas desmoglein 1 is found primarily in the superficial portion of the epidermis,
with minimal expression in oral epithelium. Patients who have developed autoantibodies directed against
desmoglein 3, with or without desmoglein 1, will histopathologically show intraepithelial clefting just above the
basal layer, and clinically oral mucosal blisters of pemphigus vulgaris will form. Patients who develop
autoantibodies directed against only desmoglein 1 will histopathologically show superficial intraepithelial clefting ofthe epidermis, but oral mucosa will not be affected. Clinically, the fine scaly red lesions of pemphigus foliaceus or
pemphigus erythematosus will be evident.
Occasionally, a pemphigus‑like oral and cutaneous eruption may occur in patients taking certain medications (e.g.,
penicillamine, angiotensin‑converting enzyme [ACE] inhibitors, nonsteroidal antiinflammatory drugs [NSAIDs]) or
in patients with malignancy, especially lymphoreticular malignancies (so‑called paraneoplastic pemphigus) (see
page 716). Similarly, a variety of other conditions may produce chronic vesiculoulcerative or erosive lesions of the
oral mucosa, and these often need to be considered in the differential diagnosis (see Table 16‑3). In addition, a rare
genetic condition termed chronic benign familial pemphigus or Hailey‑Hailey disease may have erosive cutaneous
lesions, but oral involvement in that process appears to be uncommon.
Clinical Features
The initial manifestations of pemphigus vulgaris often involve the oral mucosa, typically in adults. The average ageat diagnosis is 50 years, although rare cases may be seen in childhood. No sex predilection is observed, and the
condition seems to be more common in persons of Mediterranean, South Asian, or Jewish heritage.
Patients usually complain of oral soreness, and examination shows superficial, ragged erosions and ulcerations
distributed haphazardly on the oral mucosa (Figs. 16‑49 to 16‑52). Such lesions may affect virtually any oral mucosal
location, although the palate, labial mucosa, buccal mucosa, ventral tongue, and gingivae are often involved. Patients
rarely report vesicle or bulla formation intraorally, and such lesions can seldom be identified by the examining
clinician, probably because of early rupture of the thin, friable roof of the blisters. More than 50% of the patients have
oral mucosal lesions before the onset of cutaneous lesions, sometimes by as much as 1 year or more. Eventually,
however, nearly all patients have intraoral involvement. The skin lesions appear as flaccid vesicles and bullae (Fig.
16‑53) that rupture quickly, usually within hours to a few days, leaving an erythematous, denuded surface.
Infrequently ocular involvement may be seen, usually appearing as bilateral conjunctivitis. Unlike cicatricial
pemphigoid, the ocular lesions of pemphigus typically do not cause scarring and symblepharon formation (see page
719).
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FIG. 16-49 Pemphigus Vulgaris. Multiple erosions of the left buccal mucosa and soft palate.
FIG. 16-50 Pemphigus Vulgaris. Large, irregularly shaped ulcerations involving the floor of the mouth and ventral tongue.
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FIG. 16-51 Pemphigus Vulgaris. Multiple erosions affec ting the marginal gingiva.
FIG. 16-52 Pemphigus Vulgaris. The patient, with a known diagnosis of pemphigus vulgaris, had been treated w ith
immunosuppressive therapy. The oral erosions shown here were the only persistent manifestation of her disease.
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FIG. 16-53 Pemphigus Vulgaris. This flaccid cutaneous bulla is characteristic of skin involvement.
Without proper treatment, the oral and cutaneous lesions tend to persist and progressively involve more surface
area. A characteristic feature of pemphigus vulgaris is that a bulla can be induced on normal‑appearing skin if firm
lateral pressure is exerted. This is called a positive Nikolsky sign.
Histopathologic Features
Biopsy specimens of perilesional tissue show characteristic intraepithelial separation, which occurs just above the
basal cell layer of the epithelium (Fig. 16‑54). Sometimes the entire superficial layers of the epithelium are stripped
away, leaving only the basal cells, which have been described as resembling a “row of tombstones.” 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 (Fig. 16‑55). This feature of pemphigus vulgaris can be used in
making a diagnosis based on the identification of these rounded cells (Tzanck cells) in an exfoliative cytologic
preparation. A mild‑to‑moderate chronic inflammatory cell infiltrate is usually seen in the underlying connectivetissue.
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FIG. 16-54 Pemphigus Vulgaris. Low-power photomicrograph of perilesional mucosa aff ected by pemphigus vulgaris. An
intraepithelial cleft is located just above the basal cell layer.
FIG. 16-55 Pemphigus Vulgaris. High-power photomicrograph showing rounded, acantholytic epithelial cells sitting within the
intraepithelial c left.
The diagnosis of pemphigus vulgaris should be confirmed by direct immunofluorescence examination of fresh
perilesional tissue or tissue submitted in Michelʹs solution. With this procedure, antibodies (usually IgG or IgM) and
complement components (usually C3) can be demonstrated in the intercellular spaces between the epithelial cells
(Fig. 16‑56) in almost all patients with this disease. Indirect immunofluorescence is also typically positive in 80% to
90% of cases, demonstrating the presence of circulating autoantibodies in the patientʹs serum. Enzyme‑linked
immunosorbent assays (ELISAs) have been developed to detect circulating autoantibodies as well.
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◆ Paraneoplastic Pemphigus (Neoplasia-Induced Pemphigus;
Paraneoplastic Autoimmune Multiorgan Syndrome)Paraneoplastic pemphigus is a rare vesiculobullous disorder that affects patients who have a neoplasm, usually
lymphoma or chronic lymphocytic leukemia. Approximately 250 cases have been documented. Although the
precise pathogenetic mechanisms are unknown, some evidence suggests abnormal levels of the cytokine,
interleukin‑6 (IL‑6), could be produced by host lymphocytes in response to the patientʹs tumor. IL‑6 may then be
responsible for stimulating the abnormal production of antibodies directed against antigens associated with the
desmosomal complex and the basement membrane zone of the epithelium. In addition to a variety of differentantibodies that attack these epithelial adherence structures, some investigators have described cutaneous and
mucosal damage that appears to be mediated by cytotoxic T lymphocytes in some cases of paraneoplastic
pemphigus. As a result of this multifaceted immunologic attack, the disease manifests in an array of clinical features,
histopathologic findings, and immunopathologic findings that may be perplexing if the clinician is unfamiliar with
this condition.
Clinical Features
Patients typically have a history of a malignant lymph oreticular neoplasm, or less commonly, a benign lymph ‑
oproliferative disorder such as angiofollicular lymph node hyperplasia (Castleman disease). In approximately one‑
third of reported cases, paraneoplastic pemphigus developed before a neoplasm was identified, thus signaling the
presence of a tumor. The neoplastic disease may or may not be under control at the time of onset of the
paraneoplastic condition. Signs and symptoms of paraneoplastic pemphigus usually begin suddenly and mayappear polymorphous. In some instances, multiple vesiculobullous lesions affect the skin (Fig. 16‑57) and oral
mucosa. Palmar or plantar bullae may be evident, a feature that is uncommon in pemphigus vulgaris. For other
patients, skin lesions can appear more papular and pruritic, similar to cutaneous lichen planus. The lips often show
hemorrhagic crusting similar to that of erythema multiforme (Fig. 16‑58). Oral mucosal involvement is an early,
consistent feature of paraneoplastic pemphigus, and patients develop multiple areas of erythema and diffuse,
irregular ulceration (Fig. 16‑59), affecting virtually any oral mucosal surface. If the lesions remain untreated, then
they persist and worsen. Some patients may develop only oropharyngeal lesions, without cutaneous involvement.
FIG. 16-57 Paraneoplastic Pemphigus. The bulla and crusted ulcerations on this patient's arm are representative of the
polymorphous cutaneous lesions.
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FIG. 16-58 Paraneoplastic Pemphigus. Crusted, hemorrhagic lip lesions may be mistaken for erythema multiforme or herpes
simplex infection.
FIG. 16-59 Paraneoplastic Pemphigus. These diffuse oral ulcerations are quite painful.
Other mucosal surfaces are also commonly affected, with 70% of patients having involvement of the conjunctival
mucosa. In this area, a cicatrizing (scarring) conjunctivitis develops, similar to that seen with cicatricial pemphigoid
(Fig. 16‑60). The anogenital, nasopharyngeal, esophageal, and respiratory tract mucosa may also be involved.
Involvement of the bronchiolar mucosa is particularly significant because the lining epithelium sloughs and occludes
the bronchiolar lumina and the alveoli of the lung, resulting in a condition known as bronchiolitis obliterans.
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FIG. 16-60 Paraneoplastic Pemphigus. Ocular involvement.
Histopathologic Features
The features of paraneoplastic pemphigus on light microscopic examination may be as diverse as the clinical
features. In most cases, a lichenoid mucositis is seen, usually with subepithelial clefting (like pemphigoid) or
intraepithelial clefting (like pemphigus) (Fig. 16‑61).
FIG. 16-61 Paraneoplastic Pemphigus. This medium-power photomicrograph shows both intraepithelial and subepithelial clefting.
Direct immunofluorescence studies may show a weakly positive deposition of immunoreactants (IgG and
complement) in the intercellular zones of the epithelium and/or a linear deposition of immunoreactants at the
basement membrane zone. Although antibodies directed against desmoglein 1 and 3, as well as the bullous
pemphigoid antigens are often produced, antibodies directed against the plakin family of desmosomal components
are more commonly identified and are more specific for paraneoplastic pemphigus. ELISA or immunoblotting
techniques are used to confirm the presence of antibodies directed against periplakin or envoplakin specifically. If
these tests are not available, then indirect immunofluorescence can be conducted using a transitional type of
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epithelium (e.g., rat urinary bladder mucosa) as the substrate due to its rich expression of plakins. This technique
shows a fairly specific pattern of antibody localization to the intercellular areas of the epithelium. Examples of
paraneoplastic pemphigus that show only a lichenoid reaction with no demonstrable autoantibody production have
infrequently been described.
Treatment and Prognosis
Paraneoplastic pemphigus is often a very serious condition with a high morbidity and mortality rate, with some
series having a mortality rate of 90%. For the infrequent cases associated with a benign lymphoproliferative
condition, surgical removal of the tumor may result in regression of the paraneoplastic pemphigus. For those cases
associated with malignancy, treatment usually consists of systemic prednisone combined with cyclosporine.Cyclophosphamide, another immunosuppressive agent, may be added to this regimen, although other
immunosuppressive and immune‑modulating drugs are also being evaluated. As with pemphigus vulgaris, the skin
lesions usually respond more quickly to treatment than the oral lesions. Unfortunately, although the
immunosuppressive therapy often manages to control the autoimmune disease, this immunosuppression often
seems to trigger a reactivation of the malignant neoplasm. Thus a high mortality rate is seen, with patients
succumbing to complications of the vesiculobullous lesions, complications of immune suppressive therapy,
respiratory failure due to bronchiolitis obliterans, or progression of malignant disease. Occasionally, long‑term
survivors are reported, but these seem to be in the minority. As more of these patients are identified, therapeutic
strategies can be better evaluated and modified for optimal care in the future.
◆ Mucous Membrane Pemphigoid (Cicatricial Pemphigoid; BenignMucous Membrane Pemphigoid)Evidence has accumulated to suggest that mucous membrane pemphigoid represents a group of chronic, blistering,
mucocutaneous autoimmune diseases in which tissue‑bound autoantibodies are directed against one or more
components of the basement membrane. As such, this condition has a heterogeneous origin, with autoantibodies
being produced against any one of a variety of basement membrane components, all of which produce similar
clinical manifestations. The precise prevalence is unknown, but most authors believe that it is at least twice as
common as pemphigus vulgaris.
The term pemphigoid is used because clinically it often appears similar (the meaning of the ‑oid suffix) to
pemphigus. The prognosis and microscopic features of pemphigoid, however, are very different.
Although a variety of terms have been used over the decades to designate this condition, a group of experts from
both medicine and dentistry met in 1999 and came to an agreement that mucous membrane pemphigoid would bethe most appropriate name for the disease. Cicatricial pemphigoid, another commonly used name for this process, is
derived from the word cicatrix, meaning scar. When the conjunctival mucosa is affected, the scarring that results is
the most significant aspect of this disorder because it invariably results in blindness unless the condition is
recognized and treated. Interestingly, the oral lesions seldom exhibit this tendency for scar formation.
Clinical Features
Mucous membrane pemphigoid usually affects older adults, with an average age of 50 to 60 years at the onset of
disease. Females are affected more frequently than males by a 2 : 1 ratio. Oral lesions are seen in most patients, but
other sites, such as conjunctival, nasal, esophageal, laryngeal, and vaginal mucosa, as well as the skin (Fig. 16‑62),
may be involved.
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FIG. 16-62 Mucous Membrane Pemphigoid. Although cutaneous lesions are not common, tense bullae such as t hese may develop
on the skin of 20% of affected patients. (Courtesy of Dr. Charles Camisa.)
The oral lesions of pemphigoid begin as either vesicles or bullae that may occasionally be identified clinically (Fig.
16‑63). In contrast, patients with pemphigus rarely display such blisters. The most likely explanation for this
difference is that the pemphigoid blister forms in a subepithelial location, producing a thicker, stronger roof than the
intraepithelial, acantholytic pemphigus blister. Eventually, the oral blisters rupture, leaving large, superficial,
ulcerated, and denuded areas of mucosa (Fig. 16‑64). The ulcerated lesions are usually painful and persist for weeks
to months if untreated.
FIG. 16-63 Mucous Membrane Pemphigoid. One or more intraoral vesicles, as se en on the soft palate, may be detec ted in patients
with cicat ricial pemphigoid. Usually, ulcerations of the oral mucosa are also present.
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FIG. 16-64 Mucous Membrane Pe mphigoid. Large, irregular oral ulcerations characterize the lesions afte r the initial bullae rupture.
Often this process is seen diffusely throughout the mouth, but it may be limited to certain areas, especially the
gingiva (Fig. 16‑65). Gingival involvement produces a clinical reaction pattern termed desquamative gingivitis (see
page 148). This pattern may also be seen in other conditions, such as erosive lichen planus or, much less frequently,
pemphigus vulgaris.
FIG. 16-65 Mucous Membrane Pemphigoid. Often the gingival tissues are the only affected site, resulting in a clinical pattern
known as desquamative gingivitis. Such a pattern may also be seen with lichen planus and pemphigus vulgaris.
The most significant complication of mucous membrane pemphigoid, however, is ocular involvement. Although
exact figures are not available, up to 25% of patients with oral lesions may eventually develop ocular disease. One
eye may be affected before the other. The earliest change is subconjunctival fibrosis, which usually can be detected
by an ophthalmologist using slit‑lamp microscopic examination. As the disease progresses, the conjunctiva becomes
inflamed and eroded. Attempts at healing lead to scarring between the bulbar (lining the globe of the eye) and
palpebral (lining the inner surface of the eyelid) conjunctivae. Adhesions called symblepharons result (Fig. 16‑66).
Without treatment the inflammatory changes become more severe, although conjunctival vesicle formation is rarely
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seen (Fig. 16‑67). Scarring can ultimately cause the eyelids to turn inward (entropion). This causes the eyelashes to
rub against the cornea and globe (trichiasis) (Fig. 16‑68). The scarring closes off the openings of the lacrimal glands
as well, and with the loss of tears, the eye becomes extremely dry. The cornea then produces keratin as a protective
mechanism; however, keratin is an opaque material, and blindness ensues. End‑stage ocular involvement may also
be characterized by adhesions between the upper and lower eyelids themselves (Fig. 16‑69).
FIG. 16-66 Mucous Membrane Pemphigoid. Although the earliest ocular changes are difficult to identify, patients with ocular
involvement may show adhesions (symblepharons) between the bulbar and palpebral conjunctivae before severe ocular damageoccurs.
FIG. 16-67 Mucous Membrane Pemphigoid. The disease has cause d the upper eyelid of this patient to turn inward (entropion),
resulting in the eyelashes rubbing against the eye itself (trichiasis). Also note the obliteration of the lower fornix of the eye.
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FIG. 16-70 Mucous Membrane Pe mphigoid. Medium-power photomicrograph of perilesional tissue shows c haracteristic
subepithelial clefting.
Direct immunofluorescence studies of perilesional mucosa show a continuous linear band of immunoreactants at
the basement membrane zone in nearly 90% of affected patients (Fig. 16‑71). The immune deposits consist primarily
of IgG and C3, although IgA and IgM may also be identified. One study has suggested that, when IgG and IgA
deposits are found in the same patient, the disease may be more severe. All of these immunoreactants may play a
role in the pathogenesis of the subepithelial vesicle formation by weakening the attachment of the basement
membrane through a variety of mechanisms, including complement activation with recruitment of inflammatory
cells, particularly neutrophils.
FIG. 16-71 Mucous Membrane Pemphigoid. Direct immunofluorescence studies show a deposition of immunoreactants at the
basement membrane zone of the epithelium. (Courtesy of Dr. Ronald Grimwood.)
Indirect immunofluorescence is positive in only 5% to 25% of these patients, indicating a relatively consistent lack
of readily detectable circulating autoantibodies. One type of mucous membrane pemphigoid produces low levels of
circulating autoantibodies to epiligrin (laminin‑5), a component of the basement membrane. Antiepiligrin mucous
membrane pemphigoid seems to have more widespread involvement, affecting oral, nasal, ocular, and laryngeal
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mucosa, compared with other forms of mucous membrane pemphigoid. In contrast, another group of investigators
has shown that pemphigoid patients with only oral mucosal involvement have circulating autoantibodies to α6
integrin, a component of the hemidesmosome.
For an accurate diagnosis, perilesional tissue—rather than the ulcerated lesion itself—should be obtained. Often
the epithelium in the area of the lesion is so loosely attached that it strips off as the clinician attempts to perform the
biopsy. Such tissue is not usually adequate for diagnostic purposes because the interface between the epithelium and
connective tissue is no longer intact (although some investigators have shown positive immunofluorescence with
this tissue).
Other relatively rare conditions can mimic pemphigoid histopathologically. These include linear IgA bullous
dermatosis, angina bullosa hemorrhagica, and epidermolysis bullosa acquisita.
Linear IgA Bullous Dermatosis
Linear IgA bullous dermatosis, as the name indicates, is characterized by the linear deposition of only IgA along the
basement membrane zone. Even though some cases of mucous membrane pemphigoid may have IgA antibodies,
linear IgA bullous dermatosis predominantly affects the skin and, therefore, can usually be distinguished from
mucous membrane pemphigoid on a clinical basis.
Angina Bullosa Hemorrhagica
Angina bullosa hemorrhagica is a rare, poorly characterized oral mucosal disorder that exhibits variably painful,
blood‑filled vesicles or bullae, usually affecting the soft palate of middle‑aged or older adults (Fig. 16‑72). The
blisters typically rupture spontaneously and heal without scarring. A subepithelial cleft is noted microscopically. No
hematologic or immunopathologic abnormalities have been detected, and although the cause is unknown, manypatients have a history of trauma or corticosteroid inhaler use.
FIG. 16-72 Angina Bullosa Hemorrhagica. Hemorrhagic blisters on the soft palate in a patient w ho regularly used a c orticosteroidinhaler. (Courtesy of Dr. Peter Lyu.)
Epidermolysis Bullosa Acquisita
Epidermolysis bullosa acquisita is an immunologically mediated condition characterized by autoantibodies directed
against type VII collagen, the principal component of the anchoring fibrils. The anchoring fibrils play an important
role in bonding the epithelium to the underlying connective tissue. As a result, their immunologic destruction leads
to the formation of bullous lesions of the skin and mucosa with minimal trauma. The disease was named
epidermolysis bullosa acquisita (“acquisita” means “acquired”) because of its clinical resemblance to the inherited
condition, dystrophic epidermolysis bullosa. Unlike the inherited disorder, epidermolysis bullosa acquisita typically
affects middle‑aged or older adults.
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Oral lesions are present in nearly 50% of the cases, although such lesions are uncommon in the absence of
cutaneous lesions. To distinguish epidermolysis bullosa acquisita from other immunobullous diseases with
subepithelial clefting, a special technique is performed. A sample of the patientʹs perilesional skin is incubated in a
concentrated salt solution; this causes the epithelium to separate from the connective tissue, forming an artificially
induced bulla. Immunohistochemical evaluation shows deposition of IgG autoantibodies on the floor (connective
tissue side) of the bulla where type VII collagen resides. This finding is in contrast to that of most forms of mucous
membrane pemphigoid, in which the autoantibodies are usually localized to the roof of the induced blister.
Treatment and Prognosis
Once the diagnosis of mucous membrane pemphigoid has been established by light microscopy and directimmunofluorescence, the patient should be referred to an ophthalmologist who is familiar with the ocular lesions of
this condition for a baseline examination of the conjunctivae. This should be done whether or not the patient is
experiencing ocular complaints. In addition, if the patient is experiencing symptoms at other anatomic sites, then the
appropriate specialist should be consulted.
Because this condition is characterized by heterogeneous pathogenetic mechanisms, it is not surprising that
treatments advocated over the years have been varied. In fact, there is no single good therapy for every patient;
treatment must be individualized, depending on lesional distribution, disease activity, and therapeutic response.
Perhaps as the various forms of pemphigoid are better defined immunopathologically, more specific, directed
therapy can be devised.
Topical Agents
If only oral lesions are present, sometimes the disease can be controlled with application of one of the more potenttopical corticosteroids to the lesions several times each day. Once control is achieved, the applications can be
discontinued, although the lesions are certain to flare up again. Sometimes alternate‑day application prevents such
exacerbations of disease activity.
Patients with only gingival lesions often benefit from good oral hygiene measures, which can help to decrease the
severity of the lesions and reduce the amount of topical corticosteroids required. As an additional aid in treating
gingival lesions, a flexible mouth guard may be fabricated to use as a carrier for the corticosteroid medication.
Systemic Agents
If topical corticosteroids are unsuccessful, systemic treatments are available. Dapsone, which is a sulfa drug
derivative, can be used to treat patients with mild‑to‑moderate involvement by mucous membrane pemphigoid.
Systemic treatment with dapsone typically has fewer serious side effects when compared to systemic corticosteroid
therapy, for example.Some centers report good results with dapsone, but others observe that a minority of patients respond adequately.
Contraindications to its use include glucose‑6‑phosphate dehydrogenase deficiency or allergy to sulfa drugs.
Another alternative systemic therapy that may be used for patients with less severe disease is tetracycline or
minocycline and niacinamide (nicotinamide). Systemic daily divided doses of 0.5 to 2.0 g of each drug have been
reported (in open‑label trials) to be effective in controlling mucous membrane pemphigoid. Double‑blind, placebo‑
controlled studies on larger groups of patients should be done to confirm this form of therapy, however.
For more severely affected patients with mucous membrane pemphigoid, corticosteroids plus other
immunosuppressive/immune modulating agents, (such as, rituximab, mycophenolate mofetil, or cyclophosphamide)
may be used. This type of aggressive treatment is often indicated in the presence of advancing ocular disease, but it
must be realized that many of these patients are older and may have preexisting medical conditions that may
preclude aggressive immune suppression. Some studies have suggested that treatment with intravenous (IV) human
immunoglobulin (which is very expensive) may be more effective in managing ocular lesions of pemphigoid than
systemic corticosteroid therapy. Attempts at surgical correction of any symblepharons that might have formed must
be done when the disease is under control or quiescent; otherwise, the manipulation often induces an acute flare of
the ocular lesions.
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◆ Bullous Pemphigoid
Bullous pemphigoid is the most common of the autoimmune blistering conditions, occurring at an estimated rate
of ten cases per million population per year. The disease is characterized by the production of autoantibodiesdirected against components of the basement membrane. In many respects, bullous pemphigoid resembles mucous
membrane pemphigoid, but most investigators note that there are enough differences to consider these diseases as
distinct but related entities. One significant difference is that the clinical course in patients with bullous pemphigoid
is usually characterized by periods of remission followed by relapse, whereas the course in patients with mucous
membrane pemphigoid is usually protracted and progressive.
Clinical Features
Bullous pemphigoid typically develops in older people; most patients are between 75 and 80 years of age. No sex or
racial predilection is generally reported, although one group of investigators noted that men are overrepresented in
this disease by a 2 : 1 margin when one corrects for the skewing of the aging population toward the female gender.
Pruritus is often an early symptom. This is followed by the development of multiple, tense bullae on either normal
or erythematous skin (Fig. 16‑73). These lesions eventually rupture after several days, causing a superficial crust toform. Eventually, healing takes place without scarring.
FIG. 16-73 Bullous Pemphigoid. Cutaneous ves iculobullous lesions of the heel. The bullae eventually rupture, leaving hemorrhagiccrusted areas.
Oral mucosal involvement is uncommon, with approximately 10% to 20% of patients being affected. The oral
lesions, like the skin lesions, begin as bullae, but they tend to rupture sooner, probably as a result of the constant
low‑grade trauma to which the oral mucosa is subjected. Large, shallow ulcerations with smooth, distinct margins
are present after the bullae rupture (Fig. 16‑74).
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FIG. 16-74 Bullous Pemphigoid. These oral lesions appear as large, shallow ulcerations involving the soft palate.
Histopathologic Features
Microscopic examination of tissue obtained from the perilesional margin of a bulla shows separation of the
epithelium from the connective tissue at the basement membrane zone, resulting in a subepithelial separation.
Modest numbers of both acute and chronic inflammatory cells are typically seen in the lesional area, and the
presence of eosinophils within the bulla itself is characteristic.
Direct immunofluorescence studies show a continuous linear band of immunoreactants, usually IgG and C3,
localized to the basement membrane zone in 90% to 100% of affected patients. These antibodies bind to proteins
associated with hemidesmosomes, structures that bind the basal cell layer of the epithelium to the basement
membrane and the underlying connective tissue. These proteins have been designated as bullous pemphigoid
antigens (BP180 and BP230), and immunoelectron microscopy has demonstrated the localization of BP180 to the
upper portion of the lamina lucida of the basement membrane.In addition to the tissue‑bound autoantibodies, 50% to 90% of the patients also have circulating autoantibodies in
the serum, producing an indirect immunofluorescent pattern that is identical to that of the direct
immunofluorescence. Unlike pemphigus vulgaris, the antibody titers seen in bullous pemphigoid do not appear to
correlate with disease activity. The antibodies alone do not appear to be capable of inducing bullae in this disease.
Instead, binding of the antibodies to the basement membrane initiates the complement cascade, which in turn
results in degranulation of mast cells, with recruitment of neutrophils and eosinophils to the area. The damage to
the basement membrane is thought to be mediated by elastases and matrix metalloproteinases released by these
inflammatory cells.
Treatment and Prognosis
Treatment of patients with mild or localized bullous pemphigoid consists of application of one of the stronger
topical corticosteroid preparations. Management of the patient with moderate‑to‑severe, widespread bullouspemphigoid consists of systemic immunosuppressive therapy. Moderate daily doses of systemic prednisone
usually control the condition, after which alternate‑day therapy may be given to reduce the risk of corticosteroid
complications. If the lesions do not respond to prednisone alone, then another immunosuppressive agent (such as,
azathioprine, methotrexate, or mycophenolate mofetil) may be added to the regimen. Dapsone, a sulfa derivative,
may be used as an alternative therapeutic agent, and tetracycline and niacinamide therapy is reported to be
effective for some patients. The more severe, resistant cases require prednisone combined with cyclophosphamide;
however, this regimen has the potential for significant side effects.
The prognosis is generally good with respect to control of the skin lesions, with many patients experiencing
remission. Recent reports based on a relatively large series of bullous pemphigoid patients have suggested that
problems frequently develop due to the immunosuppressive therapy used in this older adult population. Mortality
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rates that are three times that of an age‑ and sex‑matched control population may be seen, with approximately 20%
of patients expiring 1 year after diagnosis.
◆ Erythema Multiforme
Erythema multiforme is a blistering, ulcerative mucocutaneous condition of uncertain etiopathogenesis. This is
probably an immunologically mediated process, although the cause is poorly understood. In about 50% of the cases,
the clinician can identify an apparent precipitating cause, usually a preceding infection, such as herpes simplex or
Mycoplasma pneumoniae, or less commonly, exposure to any one of a variety of drugs and medications,
particularly antibiotics or analgesics. These agents may trigger the immunologic derangement that produces the
disease. Sophisticated techniques in molecular biology have demonstrated the presence of herpes simplex DNA in
patients with recurrent erythema multiforme, thus supporting the concept of an immunologic precipitating event.
Interestingly, direct and indirect immunofluorescence studies are nonspecific and are not really very useful
diagnostically except to rule out other vesiculobullous diseases.
For many years it was thought that erythema multiforme exhibited a spectrum of severity, ranging from
erythema multiforme minor through erythema multiforme major (traditionally thought to be synonymous with
Stevens‑Johnson syndrome) and toxic epidermal necrolysis (Lyell disease). Most authorities currently feel that
erythema multiforme minor and major may represent a distinctly different process from the latter two conditions.
Therefore, Stevens‑Johnson syndrome and toxic epidermal necrolysis will be discussed separately in the next
section.
Clinical Features
Erythema multiforme typically has an acute onset and usually affects young adults in their 20s or 30s, with a slight
female predilection in current series of cases. Prodromal symptoms are often present and include fever, malaise,
headache, cough, and sore throat, occurring approximately 1 week before onset. The condition may show varying
degrees of severity in affected patients. Milder cases, known as erythema multiforme minor, usually begin with the
development of slightly elevated, round, dusky‑red patches on the skin of the extremities. These lesions may have a
variety of appearances, however (multiforme means many forms). Some of these skin lesions develop features that are
highly characteristic for the disease. These lesions appear as concentric circular erythematous rings resembling a
target or bullʹs‑eye (target lesions) (Fig. 16‑75). In more severe cases, these may evolve into bullae with necrotic
centers.
FIG. 16-75 Erythema Multiforme. The concentric erythematous pattern of the cutaneous lesions on the fingers resembles a target
or bull's-eye.
The oral cavity is the most frequently involved mucosal site, although the conjunctival, genitourinary, and
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respiratory mucosa also may be affected. Involvement of extraoral mucosal areas is usually associated with the
more severe form of this condition, erythema multiforme major.
The frequency of oral involvement is difficult to determine and is reported to range from 25% to 70%.
Discrepancies in the prevalence may be due to referral patterns or degree of scrutiny of the oral mucosa. The oral
lesions begin as erythematous patches that undergo epithelial necrosis and evolve into large, shallow erosions and
ulcerations with irregular borders (Fig. 16‑76). Hemorrhagic crusting of the vermilion zone of the lips is common
(Fig. 16‑77). These oral lesions, like the skin lesions, emerge quickly and are uncomfortable. Sometimes patients are
dehydrated because they are unable to ingest liquids as a result of mouth pain. The ulcerations often have a diffuse
distribution. The lips, labial mucosa, buccal mucosa, tongue, floor of the mouth, and soft palate are the most
common sites of involvement. Usually, the gingivae and hard palate are relatively spared.
FIG. 16-76 Erythema Multiforme. Focal hemorrhagic crusting of the lips is seen in conjunction with diffuse shallow ulcerations and
erosions involving this patient' s mandibular labial mucosa.
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FIG. 16-77 Erythema Multiforme. Same patient as Figure 16-76. Diffuse shallow ulcerations of varying sizes are noted on the right
buccal mucosa. The patient had finished a course of sulfamethoxazole and trimethoprim for a urinary tract infection a few daysbefore the onset of the lesions.
Erythema Multiforme Major
A diagnosis of erythema multiforme major can be made if two or more mucosal sites are affected in conjunction with
widespread skin lesions. In most cases the oral mucosa is involved in addition to either the ocular ( Fig. 16‑78) or
genital mucosae. With severe ocular involvement, scarring (symblepharon formation) may occur, similar to that in
cicatricial pemphigoid (see page 719).
FIG. 16-78 Erythema Multiforme Major. While involvement of other mucosal surfaces is more frequently seen with Steve ns-
Johnson syndrome, this patient's condition was preceded by oral herpetic infection. This finding, combined with his cutaneous
manifestations, resulted in a diagnosis of erythema multiforme major, in this case causing the severe conjunctivitis depicted in thisphotograph.
Histopathologic Features
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Histopathologic examination of the perilesional mucosa in erythema multiforme reveals a pattern that is
characteristic but not pathognomonic. Subepithelial or intraepithelial vesiculation may be seen in association with
necrotic basal keratinocytes (Fig. 16‑79). A mixed inflammatory infiltrate is present, consisting of lymphocytes,
neutrophils, and often eosinophils. Sometimes these cells are arranged in a perivascular orientation ( Fig. 16‑80).
Because the immunopathologic features are also nonspecific, the diagnosis is often based on the clinical
presentation and the exclusion of other vesiculobullous disorders.
FIG. 16-79 Erythema Multiforme. This medium-power photomicrograph shows inflammation and intraepithelial vesicle formation in
the basilar portion of the epithelium. Numerous necrotic and apoptotic eosinophilic keratinocytes are present in the blister area.
FIG. 16-80 Erythema Multiforme. This medium-power photomicrograph shows the perivascular inflammatory infiltrate, typically
seen in erythema multiforme.
Treatment and Prognosis
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Management of erythema multiforme, in many respects, remains controversial. In the past, the use of systemic or
topical corticosteroids was often advocated, especially in the early stages of the disease. Although there is little
good clinical evidence from controlled trials that such treatment is beneficial, this treatment is typically used at
most centers. If a causative drug is identified or suspected, then it should be discontinued immediately.
If the patient is dehydrated as a result of an inability to eat because of oral pain, then IV rehydration may be
necessary along with topical anesthetic agents to decrease discomfort.
Even though the disease is self‑limiting, usually lasting 2 to 6 weeks, about 20% of patients experience recurrent
episodes, usually in the spring and autumn. If recurrent episodes of erythema multiforme are a problem, then an
initiating factor, such as recurrent herpesvirus infection or drug exposure, should be sought. If disease is triggered
by herpes simplex, then continuous oral acyclovir or valacyclovir therapy can prevent recurrences. Veryinfrequently patients may have continuous lesions of erythema multiforme. In most cases erythema multiforme is
not life‑threatening except in its most severe form.
◆ Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
In the past, many dermatologists considered Stevens‑Johnson syndrome and toxic epidermal necrolysis to represent
the most severe end of the erythema multiforme spectrum. As careful documentation of the clinical features of these
uncommon diseases was compiled, it became evident that there were subtle, but distinct, differences between these
two conditions. Although the inciting event in erythema multiforme is usually a herpesvirus infection, Stevens‑
Johnson syndrome and toxic epidermal necrolysis are almost always triggered by drug exposure, with more than
200 different medications having been implicated. Recent studies have shown that the damage to the epithelium isdue to increased apoptosis of the epithelial cells, and several mechanisms have been postulated to account for this
phenomenon.
Clinical Features
The difference between Stevens‑Johnson syndrome and toxic epidermal necrolysis is the degree of skin
involvement, with Stevens‑Johnson syndrome having less than 10% of the body surface affected by lesions, and
toxic epidermal necrolysis having more than 30% involvement. These severe blistering diseases are rare. Stevens‑
Johnson syndrome occurs at an average rate of one to seven cases per million population per year, whereas toxic
epidermal necrolysis occurs at a rate of about one case per million per year. In
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PRINTED BY: [email protected]. Printing is for personal, private use only. No
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Violators will be prosecuted.
contrast to Stevens‑Johnson syndrome, which is usually seen in younger patients, toxic
epidermal necrolysis tends to occur in people over 60 years of age. A female predilection is
observed.These patients usually have flu‑like prodromal signs and symptoms, including fever, malaise, sore throat,
headache, and loss of appetite. Within a few days, skin lesions begin to develop, but unlike erythema multiforme, thecutaneous lesions of Stevens‑Johnson syndrome and toxic epidermal necrolysis initially appear on the trunk,
presenting as erythematous macules (completely flat). Within 1 to 14 days, however, sloughing of the skin and
flaccid bullae develop. Virtually all of these patients will have mucosal sites of involvement (Fig. 16‑81), particularly
the oral mucosa. Diffuse sloughing of a significant proportion of the skin and mucosal surfaces makes it appear as if
the patient had been badly scalded (Figs. 16‑82 and 16‑83). If the patient survives, then the cutaneous process
resolves in 3 to 5 weeks; however, oral lesions may take longer to heal, and significant residual ocular damage is
evident in half of the patients.
FIG. 16-81 Stevens-Johnson Syndrome. Genital ulcerations, demonstrated in this patient by the involvement of the glans penis,
may be a component of Stevens-Johnson syndrome, which tends to be more severe than erythema multiforme major.
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FIG. 16-82 Toxic Epidermal Necrolysis. This serious mucocutaneous disorder is characterized by diffuse bullous skin
lesions. (Courtesy of Dr. Peter Larsen.)
FIG. 16-83 Toxic Epidermal Necrolysis. The desquamation of the skin of the foot is characteristic of the diffuse sloughing
cutaneous lesions. (Courtesy of Dr. Peter Larsen.)
Histopathologic Features
Biopsy of a developing bulla of Stevens‑Johnson syndrome or toxic epidermal necrolysis typically shows a
subepithelial blister that is characterized by degenerating, necrotic basal keratinocytes. The underlying connective
tissue usually supports a rather sparse population of chronic inflammatory cells.
Treatment and Prognosis
One of the most important aspects in managing patients with Stevens‑Johnson syndrome and toxic epidermal
necrolysis is identifying and immediately discontinuing any drug that might be initiating the condition. Because the
lesions of toxic epidermal necrolysis are analogous to those suffered by burn patients, management of these patients
in the burn unit of the hospital is recommended. Corticosteroids should be avoided in the management of toxic
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epidermal necrolysis because some investigators have found that such drugs may be detrimental. IV administration
of pooled human immunoglobulins has been shown in several open‑label trials to produce remarkable resolution of
toxic epidermal necrolysis, presumably because of blockade of Fas ligand, which is believed to play a role in
inducing epithelial cell apoptosis. The mortality rate in patients with toxic epidermal necrolysis historically has been
approximately 25% to 30%; the rate in those with Stevens‑Johnson syndrome is 1% to 5%.
◆ Erythema Migrans (Geographic Tongue; Benign Migratory
Glossitis; Wandering Rash of the Tongue; Erythema AreataMigrans; Stomatitis Areata Migrans)Erythema migrans is a common benign condition that primarily affects the tongue. It is often detected on routine
examination of the oral mucosa. The lesion occurs in 1% to 3% of the population. Some epidemiologic studies have
shown that females are affected more frequently than males by a 2 : 1 ratio, whereas other series do not identify a
gender predilection. Patients occasionally may consult a health care professional if they happen to notice the unusual
appearance of their tongue or if the lingual mucosa becomes sensitive to hot or spicy foods as a result of the process.
Even though erythema migrans has been documented for many years, the etiopathogenesis is still unknown. Some
investigators have suggested that erythema migrans occurs with increased frequency in atopic individuals; however,
one large epidemiologic study in the United States found no statistically significant association between erythema
migrans and a variety of conditions that had previously been postulated either to cause or influence this process.
Erythema migrans was not seen as frequently in cigarette smokers, while there seemed to be no significant
differences in frequency related to age, sex, oral contraceptive use, presence of allergies, diabetes mellitus, or
psychological or dermatologic conditions. A similar study in Turkey essentially agreed with these findings, with the
exception of an association with a history of allergy or atopy.
Clinical Features
The characteristic lesions of erythema migrans are seen on the anterior two‑thirds of the dorsal tongue mucosa. They
appear as multiple, well‑demarcated zones of erythema (Figs. 16‑84 and 16‑85), concentrated at the tip and lateral
borders of the tongue. This erythema is due to atrophy of the filiform papillae, and these atrophic areas are typically
surrounded at least partially by a slightly elevated, yellow‑white, serpentine or scalloped border (Fig. 16‑86). The
patient who is aware of the process is often able to describe the lesions as appearing quickly in one area, healing
within a few days or weeks, and then developing in a very different area. Frequently, the lesion begins as a small
white patch, which then develops a central erythematous atrophic zone and enlarges centrifugally. Approximatelyone‑third of patients with fissured tongue (see page 11) are affected with erythema migrans as well. Some patients
may have only a solitary lesion, but this is uncommon. The lesions are usually asymptomatic, although a burning
sensation or sensitivity to hot or spicy foods may be noted when the lesions are active. Only rarely is the burning
sensation more constant and severe.
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FIG. 16-84 Erythema Migrans. The erythematous, well-demarcated areas of papillary atrophy are characteristic of erythema
migrans affecting the tongue (benign migratory glossitis). Note the asymmetrical distribution and the tendency to involve thelateral aspects of the tongue.
FIG. 16-85 Erythema Migrans. Lingual mucosa of a different patient than the one in Fig. 16-84. The lateral distribution of the
lesions is shown.
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FIG. 16-86 Erythema Migrans. Striking involvement of the dorsal and lateral surfaces of the tongue.
Very infrequently, erythema migrans may occur on oral mucosal sites other than the tongue. In these instances, the
tongue is almost always affected; however, other lesions develop on the buccal mucosa, on the labial mucosa, and
(less frequently) on the soft palate or floor of the mouth (Figs. 16‑87 and 16‑88). These lesions typically produce no
symptoms and can be identified by a yellow‑white serpentine or scalloped border that surrounds an erythematous
zone. These features should prevent confusion with such conditions as candidiasis or erythroplakia.
FIG. 16-87 Erythema Migrans. Lesions of the lower labial mucosa.
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FIG. 16-88 Erythema Migrans. These palatal lesions show well-demarcated erythematous areas surrounded by a white border,
similar to the process involving the tongue.
Histopathologic Features
If a biopsy specimen of the peripheral region of erythema migrans is examined, a characteristic histopathologic
pattern is observed. Hyperparakeratosis, spongiosis, acanthosis, and elongation of the epithelial rete ridges are seen
(Fig. 16‑89). In addition, collections of neutrophils (Munro abscesses) are observed within the epithelium (Fig. 16‑
90); lymphocytes and neutrophils involve the lamina propria. The intense neutrophilic infiltrate may be responsible
for the destruction of the superficial portion of the epithelium, thus producing an atrophic, reddened mucosa as the
lesion progresses. Because these histopathologic features are reminiscent of psoriasis, this is called a psoriasiform
mucositis. Despite the apparent lack of association between dermatologic conditions and erythema migrans in some
reports, at least one case‑control study of psoriatic patients showed that erythema migrans occurred at a rate of
about 10%; only 2.5% of an age‑matched and sex‑matched population were affected. A Brazilian study determined
that both patients with psoriasis and those with benign migratory glossitis were more likely to have the same humanleukocyte antigen (HLA) group, namely HLA‑Cw6. Whether these findings mean that erythema migrans represents
oral psoriasis or that patients with psoriasis are just more susceptible to erythema migrans is open to debate.
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FIG. 16-89 Erythema Migrans. This low-power photomicrograph shows the elongation of the rete ridges with parakeratosis and
neutrophilic infiltration. Such features are also common in psoriasis, which explains why this is known as a psoriasiform
mucositis.
FIG. 16-90 Erythema Migrans. This medium-power photomicrograph shows collections of neutrophils in the superficial spinous
layer of the epithelium.
Treatment and Prognosis
Generally no treatment is indicated for patients with erythema migrans. Reassuring the patient that the condition is
completely benign is often all that is necessary. Infrequently, patients may complain of tenderness or a burning
sensation that is so severe that it disrupts their lifestyle. In such cases, topical corticosteroids, such as fluocinonide or
betamethasone gel, may provide relief when applied as a thin film several times a day to the lesional areas.
◆ Reactive Arthritis (Reiter Syndrome)
Reactive arthritis represents a group of uncommon diseases that most likely have an immunologically mediated
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cause. Current evidence suggests that these disorders may be triggered by any one of several infectious agents in a
genetically susceptible person. In some instances, the arthritis will be accompanied by mucocutaneous findings,
including oral lesions. A classic triad of signs has been described:
1. Nongonococcal urethritis
2. Arthritis
3. Conjunctivitis
However, most patients do not exhibit all three of these signs. Although reactive arthritis with a mucocu taneous
component is also known as Reiter syndrome, some authors have advocated removing the Reiter eponym because of
Hans Reiterʹs Nazi criminal activities during World War II, and he was not the first to describe this syndrome.
It is interesting that reactive arthritis has been reported with some frequency in patients infected with the humanimmunodeficiency virus (HIV).
Clinical Features
Reactive arthritis is particularly prevalent in young adult men. In some series, a male‑to‑female ratio of up to 9 : 1 has
been reported. The majority (60% to 80%) of these patients are positive for HLA‑B27, a haplotype present in only 10%
of the population. The syndrome usually develops 1 to 4 weeks after an episode of dysentery or venereal disease; in
fact, two French physicians published a description of this entity affecting four postdysenteric soldiers 1 week before
Reiterʹs paper appeared.
Urethritis is often the first sign and is seen in both affected males and females. Females may also have
inflammation of the uterine cervix. Conjunctivitis usually appears concurrently with the urethritis, and after several
days, arthritis ensues. The arthritis usually affects the joints of the lower extremities, although TMJ involvement has
been identified in one‑third of these patients, typically as erosion of the condylar head. Skin lesions often take theform of a characteristic lesion of the glans penis (balanitis circinata). These lesions develop in about 20% to 30% of
patients with reactive arthritis, and they appear as well‑circumscribed erythematous erosions with a scalloped,
whitish linear boundary.
The oral lesions, which occur in slightly less than 20% of patients with this disorder, are described in various ways.
Some reports mention painless erythematous papules distributed on the buccal mucosa and palate; other reports
describe shallow, painless ulcers that affect the tongue, buccal mucosa, palate, and gingiva. Some authors have even
implied that geographic tongue may be a component of reactive arthritis, probably because geographic tongue bears
a superficial resemblance to the lesions of balanitis circinata.
The American Rheumatism Association has defined reactive arthritis based on the clinical findings of a peripheral
arthritis that lasts longer than 1 month in conjunction with urethritis, cervicitis, or both.
Histopathologic Features
The histopathologic findings of the cutaneous lesions in patients with reactive arthritis are frequently similar to those
found in patients with psoriasis, particularly with respect to the presence of microabscesses within the superficial
layers of the surface epithelium. Other features in common with psoriasis include hyperparakeratosis with
elongated, thin rete ridges.
Treatment and Prognosis
Some patients with reactive arthritis experience spontaneous resolution of their disease after 3 to 12 months, but
many others have chronic symptoms that may wax and wane. Treatment may not be necessary for the milder cases.
NSAIDs are initially used for managing arthritis, and sulfasalazine may be helpful in resolving cases that do not
respond. Immunosuppressive or immune modulating agents, including corticosteroids, azathioprine, etanercept,
and methotrexate, are reserved for the most resistant cases if they are not associated with HIV infection.Physical therapy probably helps to reduce joint fibrosis associated with arthritis. About 15% to 20% of patients
with this disorder have severe disability, usually from arthritis.
◆ Lichen Planus
Lichen planus is a relatively common, chronic dermatologic disease that often affects the oral mucosa. The strange
name of the condition was provided by the British physician Erasmus Wilson, who first described it in 1869. Lichens
are primitive plants composed of symbiotic algae and fungi. The term planus is Latin for flat. Wilson probably
thought that the skin lesions looked similar enough to the lichens growing on rocks to merit this designation. Even
though the term lichen planus suggests a flat, fungal condition, current evidence indicates that this is an
immunologically mediated mucocutaneous disorder.
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A variety of medications may induce lesions that can appear clinically very similar to the idiopathic form of the
condition; however, the term lichenoid mucositis (or lichenoid dermatitis, depending on the site involved) is
probably a better name for the drug‑related alterations (see page 317). Similarly, foreign material that becomes
inadvertently embedded in the gingiva may elicit a host response that is termed lichenoid foreign body gingivitis
(see page 146). Reports of hepatitis C infection associated with oral lichen planus occasionally have appeared in the
literature, usually from the Mediterranean countries, but this does not appear to be a significant association in the
United States or Great Britain. More recent, carefully controlled epidemiologic studies do not appear to support an
association of oral lichen planus with hepatitis C. However, genetic influences presumably may have an effect on the
expression of lichen planus in select populations.
The relationship of stress or anxiety to the development of lichen planus is controversial, and most cited casesappear to be anecdotal or lack appropriate controls. Those studies that have applied psychologic questionnaires
often find increased levels of anxiety in these patients; however, many patients who have been told that they have
lichen planus are aware that anxiety has been linked to the disorder. Whether this awareness may influence the
manner in which they answer the psychologic questionnaires could be debated. In one study that used psychologic
questionnaires to attempt to resolve this question, patients with oral lichen planus had no greater degree of stress in
their lives than did age‑matched and sex‑matched control patients. It might be that stress has no bearing on the
pathogenesis of lichen planus; however, an alternative explanation might be that those patients who have lichen
planus simply respond in this fashion to levels of stress that do not induce lesions in other people.
Clinical Features
Most patients with lichen planus are middle‑aged adults. It is rare for children to be affected. Women predominate
in most series of cases, usually by a 3 : 2 ratio over men. Approximately 1% of the population may have cutaneouslichen planus. The prevalence of oral lichen planus is between 0.1% and 2.2%.
The skin lesions of lichen planus have been classically described as purple, pruritic, polygonal papules (Fig. 16‑91).
These usually affect the flexor surfaces of the extremities. Excoriations may not be visible, despite the fact that the
lesions itch, because it hurts the patient when he or she scratches them.
FIG. 16-91 Lichen Planus. The cutaneous lesions on the wrist appear as purple, polygonal papules.
Careful examination of the surface of the skin papules reveals a fine, lacelike network of white lines (Wickham
striae) (Fig. 16‑92). Other sites of extraoral involvement include the glans penis, the vulvar mucosa, and the nails.
Essentially there are two forms of oral lesions: reticular and erosive.
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FIG. 16-92 Lichen Planus. Closer view of a skin lesion of lichen planus. Careful examination shows a network of fine white lines
(Wickham striae) on the surface of the papules.
Reticular Lichen Planus
Reticular lichen planus is much more common than the erosive form, but the erosive form predominates in several
studies. This is probably because of referral bias (because the erosive form is symptomatic and, therefore, the patient
is more likely to be referred to an academic center for evaluation). The reticular form usually causes no symptoms
and involves the posterior buccal mucosa bilaterally (Fig. 16‑93). Post‑inflammatory melanosis occasionally
accompanies the reticular striae, particularly in persons of color (Fig. 16‑94). Other oral mucosal surfaces may also be
involved concurrently, such as the lateral and dorsal tongue, the gingivae, the palate, and vermilion border (Fig. 16‑
95).
FIG. 16-93 Lichen Planus. The interlacing white lines and papules are typical of reticular lichen planus involving the buccal
mucosa, the most common site of oral involvement.
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FIG. 16-96 Lichen Planus. A, A middle-aged woman with mild reticular lichen planus of the left buccal mucosa. B, Same patient 2
weeks later, showing exacerbation of the lesions. Such waxing and waning is characteristic of lichen planus.
FIG. 16-97 Lichen Planus. With involvement of the dorsal tongue by reticular lichen planus, the characteristic interlacing striae
seen in the buccal mucosal lesions are usually not present. Instead, smooth white plaques are typically observed replacing thenormal papillary surface of the tongue.
Erosive Lichen Planus
Erosive lichen planus, although not as common as the reticular form, is more significant for the patient because the
lesions are usually symptomatic. Clinically, there are atrophic, erythematous areas with central ulceration of varying
degrees. The periphery of the atrophic regions is usually bordered by fine, white radiating striae ( Figs. 16‑98 and 16‑
99). Sometimes the atrophy and ulceration are confined to the gingival mucosa, producing the reaction pattern called
desquamative gingivitis (see page 148) (Fig. 16‑100). In such cases, biopsy specimens should be obtained for light
microscopic and immunofluorescent studies of perilesional tissue, because mucous membrane pemphigoid (see page718) and pemphigus vulgaris (see page 712) may appear in a similar fashion.
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FIG. 16-98 Lichen Planus. Ulceration of the buccal mucosa shows peripheral radiating keratotic striae, characteristic of oral
erosive lichen planus.
FIG. 16-99 Lichen Planus. A, The dorsal surface of the tongue shows extensive ulceration caused by erosive lichen planus. Note
the fine white streaks at the periphery of the ulcerations. B, Same patient after systemic corticosteroid therapy. Much of themucosa has reepithelialized, with only focal ulcerations remaining.
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FIG. 16-100 Lichen Planus. Erosive lichen planus often appears as a desquamative gingivitis, producing gingival erythema and
tenderness.
If the erosive component is severe, epithelial separation from the underlying connective tissue may occur. This
results in the relatively rare presentation of bullous lichen planus.
Histopathologic Features
The histopathologic features of lichen planus are characteristic but may not be specific, because other conditions,
such as lichenoid drug reaction, lichenoid amalgam reaction, oral graft‑versus‑host disease (GVHD), lupus
erythematosus (LE), chronic ulcerative stomatitis, and oral mucosal cinnamon reaction may also show a similar
histopathologic pattern. Varying degrees of orthokeratosis and parakeratosis may be present on the surface of the
epithelium, depending on whether the biopsy specimen is taken from an erosive or reticular lesion.
The thickness of the spinous layer can also vary. The rete ridges may be absent or hyperplastic, but they classically
have a pointed or “saw‑toothed” shape (Fig. 16‑101).
FIG. 16-101 Lichen Planus. A, This low-power photomicrograph of an oral lesion shows hyperkeratosis, saw-toothed rete ridges,
and a bandlike infiltrate of lymphocytes immediately subjacent to the epithelium. B, Higher-power view showing migration of lymphocytes into the lower epithelium with interface degeneration of the basal cell layer.
Destruction of the basal cell layer of the epithelium (hydropic degeneration) is also evident. This is accompanied
by an intense, bandlike infiltrate of predominantly T lymphocytes immediately subjacent to the epithelium (Fig. 16‑
102). Degenerating keratinocytes may be seen in the area of the epithelium and connective tissue interface and have
been termed colloid, cytoid, hyaline, or Civatte bodies. No significant degree of epithelial atypia is expected in oral
lichen planus, although lesions having a superimposed candidal infection may appear worrisome. These should be
reevaluated histopathologically after the candidal infection is treated. On occasion, the chronic inflammatory host
response to the atypical cells of epithelial dysplasia can appear virtually indistinguishable histopathologically from
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mucosa. Antifungal therapy is necessary in such a case. Some investigators recommend annual reevaluation of the
reticular lesions of oral lichen planus.
Erosive lichen planus is often bothersome because of the open sores in the mouth. Because it is an
immunologically mediated condition, corticosteroids are recommended. The lesions respond to systemic
corticosteroids, but such drastic therapy is usually not necessary. One of the stronger topical corticosteroids (e.g.,
fluocinonide, betamethasone, or clobetasol gel) applied as a thin film several times per day to the most symptomatic
areas is usually sufficient to induce healing within 1 or 2 weeks. The patient should be warned that the condition will
undoubtedly flare up again, in which case the corticosteroids should be reapplied. In addition, the possibility of
iatrogenic candidiasis associated with corticosteroid use should be monitored (Fig. 16‑104). Some investigators have
recommended compounding corticosteroid ointments with an adhesive methylcellulose base, but patient compliancemay be reduced because this material is difficult to apply. Although the use of agents (such as, topical retinoids,
tacrolimus, mycophenolate mofetil, or cyclosporine) has occasionally been advocated for recalcitrant cases of erosive
lichen planus, reports of their efficacy have usually been limited to small series of cases or have been contradictory.
Furthermore, their side effects can be significant, and in the case of tacrolimus or cyclosporine, the cost of the drug
may be prohibitive. Some investigators suggest that patients with oral erosive lichen planus be evaluated every 3 to 6
months, particularly if the lesions are not typical.
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