ARTICLE
Auteur(s) : Marcello Menta Simonsen Nico1,
Maria Apparecida Constantino Vilela1, Evandro Ararigbóia
Rivitti1, Silvia
Vanessa Lourenço1,2
1Department of Dermatology, Hospital das Clínicas,
Medical School; University of São Paulo, Brazil
2Department of Pathology, Faculdade de Odontologia da
Universidade de São Paulo, Av Prof Lineu Prestes, 2227, Cidade
Universitária, São Paulo, CEP: 05508-000, SP-Brazil
accepté le 5 Decembre 2007
Oral lesions occurring during the course of lupus erythematosus
(LE) have long been described in dermatological, rheumatological
and dental literature [1, 2]. Many attempts have been made to
correlate these manifestations with the prognosis of systemic LE
(SLE) (oral ulcerations are included among the American College of
Rheumatology criteria for systemic LE) [3], but conclusions vary.
Reproducible criteria in the classification of oral lesions in LE
are lacking and as a consequence, comparison between existing
studies is hampered.
Oral lesions in lupus erythematosus
Different studies of oral lesions in the course of LE have shown a
frequency varying from 9 to 45% in systemic disease and 3 to 20% in
localized cutaneous disease [4-6]. Our group reported 26 patients
with oral lesions among 188 LE patients studied, 13 of these had
SLE according to the ACR criteria. Nineteen patients were female
and 7 were male [7]. Burge et al. reported 10 female and 4 male
patients with oral lesions of LE, of these, 5 were considered to
have SLE and 9 had localized cutaneous LE [1]. In a further study
by our group, oral lesions were diagnosed in 46 patients, only 13
had SLE according to established criteria [8]. A possible reason
for the lower frequency of oral lesions when compared with skin
lesions may be the lack of ultraviolet radiation incidence in the
oral cavity in contrast to the skin.
Clinical descriptions of oral LE lesions vary enormously in the
different studies. Terms used include: “oral discoid lesion”,
“chronic plaque”, “lupus cheilitis”, “acute ulcer”, “oral ulcer”,
“red ulcer”, “ulcerative plaques”, “pebbly red areas”, “honeycomb
lesion”, “keratotic lesion” “white keratotic plaques”, “purpuric
lesions” and “diffuse palatal petechial erythema” [2, 3, 9-12].
Thus, in contrast to cutaneous LE, no uniformity exists in
classifying oral LE lesions, and an adequate clinical
categorization is lacking.
Additionally and yet more confusing, oral ulcerations in LE
patients have for a long time been considered as a sign of
“vasculitis” and predictors of severe systemic flares of the
disease [12, 13]. This misconception brings no light to the
knowledge of such lesions and has created myths among physicians
about the true significance of oral lesions of LE.
Classification of oral LE and correlation with cutaneous
LE
Cutaneous manifestations of LE are divided in non-specific
(non-diagnostic lesions) and specific (diagnostic lesions) [14].
Non-specific lesions usually indicate systemic disease with
consequent cutaneous repercussions and include vasculitis,
Raynaud’s phenomenon, non-scarring alopecia and livedo racemosa.
Non-specific manifestations are not observed in the oral cavity.
Specific LE lesions indicate lupus dermatitis (analogous to
“lupus arthritis”, “lupus nephritis”, “lupus serositis” etc) and
are represented by interface dermatitis. These are classified as
cutaneous acute, subacute and chronic LE [14, 15]. These categories
represent variants of the lupus process on the skin, with specific
clinical, histopathological, genetic and immunoserological features
[14-16].
As with many other skin diseases with mucosal manifestations,
oral lesions of LE represent the exact mucosal counterpart of skin
lesions, and should be similarly classified. The greatest
difficulty in analyzing oral LE lesions lies in the fact that
mucosal clinical responses are morphologically more limited than
their skin analogues: scales are not observed due to moisture,
there are no pilo-sebaceous units (consequently no “follicular
pluggings”, so typical of discoid LE) and scarring (atrophy) is
difficult to assess because of better mucosal regeneration when
compared to skin. Moreover, some patients may present with
exclusively oral lesions, making an immediate correlation with
cutaneous LE less obvious.
Chronic lesions
Chronic cutaneous LE (CCLE) includes, among others, the classic
discoid lesion. This is characterized by round, well-circumscribed,
infiltrated, scaly and atrophic plaques with follicular plugging,
mainly on the face, scalp, ears, and, more rarely, on the chest and
arms (disseminated discoid LE) (figure 1A). Discoid
lesions develop severe scarring in most cases; scalp lesions
typically show scarring alopecia. Verrucous LE refers to intensely
keratotic discoid lesions. Other variants of CCLE include tumid,
lupus panniculitis and chilblain LE [14, 16, 17].
The commonest mucosal presentation of chronic LE is the oral
discoid lesion. The typical clinical picture is of a
well-demarcated, round or irregular red area that can be atrophic
or ulcerated, with white radiating keratotic striae and
telangiectases. This aspect represents the very same lesion as the
classic cutaneous discoid LE (figure 1B and C).
Morphologic variants of chronic oral LE include the so-called
“honeycomb plaques” (a clinical aspect of mucosal scarring) (figure 2A) [1]
intensely keratotic white lesions (corresponding to verrucous CCLE)
(figure 2B), and
linear fissured, ulcerative and keratotic lesions that may occur in
buccal mucosa [10]. Most patients will have simultaneous cutaneous
lesions, but exclusive mucosal manifestations are not rare.
Isolated palatal lesions can be seen (figure 1C). Pain is
variable. Lesions are more often asymmetrically distributed in the
oral cavity (palate, buccal mucosa, tongue). This asymmetry is
important in differential diagnosis since lesions of clinically
similar diseases such as oral lichen planus (LP) are almost always
symmetric. Tumid and subcutaneous chronic LE have not been
described in the oral cavity.
Lip involvement is frequent. Clinical manifestations include
well-demarcated discoid lesions or a diffuse cheilitis [2]. Lesions
typically tend to spread from the vermilion to the surrounding lip
skin, obscuring the limits of the vermilion (figure 3A and B). This
feature is useful in differentiating LE from lichen planus of the
lip and from other types of cheilitis, as LP lesions are
characteristically limited to the vermilion area. The designation
“lupus cheilitis” is used at times [1, 2], but it may suggest a
different or special manifestation instead of a typical LE lesion
on that location.
Squamous cell carcinoma may, rarely, arise in longstanding
scarring lesions of oral LE, as well as in long established scars
of other chronic mucosal diseases (LP, syphilis) [14, 16] (figure 3C).
Subacute lesions
Subacute LE represents a subtype of LE with characteristic
clinical, serological and prognostic features [14]. Subacute
cutaneous LE (SCLE) includes psoriasiform
(erythemato-papulo-squamous) and polycyclic (erythema
multiforme-like) photosensitive eruptions and is more commonly
associated to mild systemic disease (figure 4A). “Rowell’s
Syndrome” refers to the coexistence of erythema multiforme and LE,
but its identity is widely discussed. Subacute LE lesions heal
without scarring; vitiligo-like hypo pigmentation is common [14,
16, 17]. Although SCLE lesions characteristically appear on
sun-exposed areas, intra oral manifestations may rarely be present.
Lesions consist of well-demarcated, round, red patches that on
close inspection may appear slightly depressed. Due to moisture,
scaling is not evident (figure 4B). Lip lesions
may occur as diffuse erythematous scaling plaques on the vermilion
that typically spread towards the skin of the lip and are almost
always associated with more generalized SCLE (figure 3B).
Acute lesions
Acute cutaneous LE (ACLE) includes the classic malar edematous
butterfly lesion (figure
5A), a corresponding widespread eruption and bullous LE.
These presentations almost always indicate systemic LE, with its
diagnostic serological changes and manifestations in other organs.
These cutaneous lesions tend to heal without scarring since
inflammatory component is scarce [14-18]. Oral lesions in the
setting of systemically ill LE patients are very common. There are
many possible clinical presentations: circumscribed red macules,
diffuse or palatal erythema, purpuric macules (figure 5B), and erosions
or ulcerations that may or may not be symmetrically distributed in
the mucosa [2, 14]. These can occasionally be present in the
absence of skin lesions.
There is still controversy as to whether bullous LE represents
specific acute or non-specific LE dermatitis [14] but
histopathological and immunofluorescence data [14-16] favor
specific acute manifestation because they are diagnostic. Patients
with bullous LE may present with linearly arranged blisters along
the lip vermilion or with intact or, more often, ruptured blisters
on the palate or buccal mucosa [21] (figures 6A and B). There
is a rare variant of LE in which lesions have a widespread erosive
bullous aspect similar to Stevens-Johnson disease or toxic
epidermal necrolysis, these patients usually present with
hemorrhagic crusts and erosions on the lips and mucous epithelial
detachment. The question as to whether these manifestations
represent a hyper-acute type of specific lupus dermatitis/mucositis
or a non-specific indicator of severe activity is still under
debate [19, 20].
Oral ulcerations or ulcers in the setting of SLE have long been
considered to be predictors of systemic vasculitis and worse
prognosis [12, 13]. Jorizzo et al. proved that these lesions
represent, in fact, specific lupus lesions clinically and
histopathologically (interface mucositis), without prognostic
implications [18] (figure 7). Curiously,
though, the same group of authors, in a latter review, stated that
these ulcers are non-specific manifestations of SLE heralding
serious disease. However, no explanation is offered on their nature
or histopathological findings [22]. Established prognostic indexes
for systemic LE in the rheumatological literature, such as the
“Systemic Lupus Activity Measure” (SLAM) [11, 12], equivocally
classify oral LE ulcers together with “peri-ungueal erythema,
photosensitive rash and nail fold infarcts” (mostly non specific LE
lesions), and separated from “erythematous rash, discoid lesions,
lupus paniculitis, bullous lesions” (specific LE lesions). This
classification probably provides unnecessary additional value to
muco-cutaneous specific LE lesions in establishing systemic
prognosis. These oral lesions of LE are summarized in table 1.
Table 1 Clinical presentations of oral LE lesions
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Chronic lesions: discoid lesions
|
Subacute lesions
|
Acute lesions
|
- Note- lesions are almost always asymmetrically distributed on
buccal cavity.
- – Atrophic or ulcerated round lesions with peripheral
keratotic striae (figure 1B)
- – Linear ulcers with keratotic striae.
- – “Honeycomb plaques” (longstanding scarring lesions)
(figure 2A).
- – Intensely keratotic lesions
- (verrucous LE) (figure 2B).
- – palatal discoid lesions (figure 1C).
- – Labial discoid lesions (figure 3A).
- – Squamous cell carcinoma may arise in longstanding
scarring lesions (figure 3C).
|
- – Discrete red patches, (much rarer and more discrete than
cutaneous subacute LE) (figure 4B).
- – Diffusely scaly labial patches (figure 3B).
|
- – Erythemato-purpuric macules (figure 5B).
- – Palatal erythema.
- – Petechiae.
- – Ulcerations (figure 7A).
- – Bullous LE: labial blisters (figure 6A), intra-oral
intact or ruptured blisters (figure 6B).
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Clinical differential diagnosis
Clinical differential diagnosis of LE mucositis will depend on the
morphology of the lesion analyzed. The main differential diagnoses
for keratotic discoid lesions are LP, lichenoid reactions to dental
fillings, traumatic and smoker’s keratoses, and verrucous
carcinoma. Ulcerated discoid lesions should be differentiated from
aphtha, erosive LP, traumatic ulcers, deep mycoses, Langerhans
cells histiocytosis and SCC (SCC can develop in old scarring LE
lesions). Lip lesions may simulate contact cheilitis, factitious
cheilitis, actinic cheilitis, LP, psoriasis, erythema multiforme,
pemphigus vulgaris and SCC. Erythematous or purpuric macules may
resemble LP, erythema multiforme, mucous patches of syphilis,
petechiae of viral exanthem, and negative pressure purpura
(“fellatio syndrome”). Finally, differential diagnoses for oral
bullous LE include pemphigus vulgaris, mucous membrane pemphigoid,
herpes simplex, varicella, and erythema multiforme with its
variants (Stevens-Johnson disease and toxic epidermal necrolysis).
Histopathological aspects
Several studies have focused on the histopathological aspects (figures 8A-C) of
cutaneous and mucosal lesions of LE [5, 7-9, 15, 16, 23, 24].
Characteristically, features of cutaneous and mucosal LE are of
perivascular and interface dermatitis/mucositis.
Histopathological distinction between acute, subacute and
chronic cutaneous LE lies in the intensity of epithelial affection,
severity of follicular damage, nature and level of the inflammatory
infiltrate in the dermis [15, 16, 24]. The histopathologic features
of oral LE represent the mucosal counterpart to the described
aspects of cutaneous LE. The most important differences lie in the
absence of pilo-sebaceous units and the frequent finding of an
absent epithelium that may be lost during the biopsy procedure or
due to the high frequency of ulcerated lesions inside the mouth
(marked basal cell liquefaction associated with mechanical trauma).
In a study of 46 oral LE patients by our group, the most consistent
findings corresponded to an interface mucositis with a superficial
and deep perivascular lymphocytic inflammation; edema in the lamina
propria is constantly present. The covering epithelium presented
areas of acanthosis alternated with areas of atrophy. Occasional
pseudo-epitheliomatous hyperplasia was observed. Variable degrees
of spongiosis were present (a common finding in oral mucosa
biopsies, not important for diagnosis). Foci with hydropic
degeneration of the basal layer were evident. Basal necrotic
keratinocytes, widespread or focal, were frequent. Thickening of
epithelial and vascular basement membranes was visible on
haematoxilin-eosin (HE) and PAS stains [8, 9]. The presence of
epithelial atypia is not rare and has been observed by other
authors [18]. This is probably due to a hyperproliferative status
of the mucosa as demonstrated by our and previous studies using
immunohistochemical labelling of cytokeratins [7, 25]. Occasional
interlobular minor salivary gland inflammation is present, and this
has been inappropriately labelled “Sjögren’s syndrome associated
phenomenon” [3, 22].
Histopathological changes in mucosal LE lesions must be
differentiated from similar alterations that may occur in other
instances of perivascular and interface mucositis, such as lichen
planus (LP), lichenoid mucositis and drug reactions [16, 23].
Karjalainen et al. compared histopathological features of oral LE
with those of LP and concluded that the most important differences
included: thicker basement membrane in LE (HE and PAS), edema in
the lamina propria more pronounced in LE, PAS positive thickening
of blood vessel walls in LE, deeper perivascular infiltrates in LE,
more pronounced epithelial atrophy in LP [9]. The presence of mucin
in the lamina propria is an important clue in differentiating LE
from LP [14, 16]. These differences are summarized in table 2.
Jorizzo et al. [18] studied 10 patients diagnosed with SLE who
presented with oral ulcers. These authors demonstrated that all
biopsies of these ulcers revealed interface LE mucositis with no
sign of vasculitis, these findings demonstrate that oral ulcers in
SLE represent the ulcerated form of specific LE mucositis, probably
without prognostic implications [18] (figure 7B), contrary to
the view that these lesions could indicate systemic vasculitis and
have prognostic implications [3, 11-13].
Table 2 Histopathological comparison between oral LE,
oral LP and oral lichenoid drug reactions
|
Oral LE
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Oral LP
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Lichenoid drug reactions
|
|
Epithelial alterations
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Hyperkeratosis, granulosis, acanthosis and atrophy, spongiosis,
hydropic degeneration (patchy or widespread), colloid bodies,
hyperproliferation of basal layer, sometimes with presence of
atypical keratinocytes.
|
Hyperkeratosis, granulosis, acanthosis and atrophy, epithelial
cones in “saw-tooth”, spongiosis, hydropic degeneration (patchy or
widespread). In severe cases, complete destruction of basal layer
is seen.
|
Hyperkeratosis, granulosis, acanthosis and atrophy, marked
spongiosis, hydropic degeneration (generally widespread necrosis up
to suprabasal layers).
|
|
Basement membrane (epithelial and vascular wall)
|
Regular or focal thickening of epithelial basement membrane
associated with thickening of vascular wall.
|
Focal or widespread destruction of basement membrane by
inflammatory infiltrate.
|
Widespread destruction of basement membrane by inflammatory
infiltrate.
|
|
Lamina propria
|
Lymphocytic predominant inflammatory infiltrate of variable
intensity with limited or widespread aggression to the basal
keratinocytes. Inflammatory infiltrate is seen both in the
superficial lamina propria (lichenoid) and deep perivascular.
Vessel walls are prominent with endothelial tumefaction. Edema and
variable deposits of mucin are present.
|
Lymphocytic predominant lichenoid infiltrate with presence of
Langerhans cells.
|
Heavy lymphocytic predominant lichenoid infiltrate, with presence
of eosinophils. Inflammatory infiltrate may be present around
vessels in mid and deep lamina propria. Prominent interstitial
edema and vascular congestion are present.
|
Immunofluorescence studies
Direct Immunofluorescence (DIF) studies are often performed when
diagnosing cutaneous and mucosal lesions of LE [24, 26-28]. These
are particularly useful in differential diagnosis between LE and
other possibly similar clinical and histopathological conditions
such as LP. The three major classes of immunoglobulins IgG, IgA and
IgM as well as complement components may be found in basement
membrane zone deposits of cutaneous and oral LE, in a linear and/or
granular pattern [24, 26-28]. DIF in oral LE lesions is frequently
positive and the most commonly identified immuno-reactants are IgM
and C3, the most common immuno-reactive patterns include colloid
(apoptotic) bodies and continuous (linear) or granular basement
membrane fluorescence that can be found on up to 100% of biopsies
studied [7, 8]. These findings can also be found in other diseases
and in sun damaged skin and thus are considered non-specific. IgG
and IgA immuno-reactivity is most specific for LE, typically in
linear basement membrane pattern. These are observed on up to 29%
of oral lesions [26].
Conclusion
Oral lesions are not a rare event in the clinical context of LE.
These are better understood if considered as the mucosal
counterpart of cutaneous LE (“lupus dermatitis” and “lupus
mucositis”), for they represent those very same lesions in the
mucosa. Identical to cutaneous LE, clinical and histopathological
subtypes of oral LE lesions represent diversity in intensity and in
chronological phases of interface inflammation on the mucosa [15,
29]. When compared to cutaneous LE, differences concern mostly the
anatomic and functional peculiarities of oral tissues: lack of
pilo-sebaceous units, lack of scaling due to moisture and frequent
ulceration due to friction. These limitations make use of strict
clinical-pathological criteria essential for differentiating oral
LE from other possibly similar conditions such as LP, and other
lichenoid eruptions such as drug reactions. There is no definite
evidence that oral LE lesions of any type may herald a worse
outcome or systemic vasculitis.
Acknowledgements
FAPESP grant 03/04880-3. Conflict of interest: none.
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