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    1/26/2016 Bookshelf: Oral and Maxillofacial Pathology

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    PRINTED BY: [email protected]. Printing is for personal, private use only. No

    part of this book may be reproduced or transmitted without publisherʹs prior permission.

    Violators will be prosecuted.

    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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    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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