Seminars in Diagnostic Pathology 34 (2017) 237–249

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Seminars in Diagnostic Pathology

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Lichenoid and interface dermatoses

Alejandro A. Gru a,n, Andrea L. Salavaggione b
a
Department of Pathology & Dermatology, University of Virginia, Charlottesville, VA, Unitee States
b
Department of Radiation Oncology, The Ohio State University, Columbus, OH, United States

art ic l e i nf o a b s t r a c t

The terms ‘lichenoid’ and ‘interface’ dermatitis are often used interchangeably to describe an in-
Keywords: flammatory pattern characterized histologically by damage to the basal keratinocytes in the epidermis.
Lichen planus The mechanism of cell damage of such cells is now best understood as apoptosis, or programmed cell
Lupus erythematosus death. This inflammatory pattern of dermatoses, is also accompanied frequently by a band of lympho-
Erythema multiforme cytes and histiocytes in the superficial dermis, that often obscures the dermal-epidermal junction, hence
Graft versus host disease the term ‘lichenoid’. A discussion of the more common lichenoid/interface dermatitides encountered in
the routine clinical practice encompasses the following entities: lichen planus, lupus erythematosus,
dermatomyositis, erythema multiforme, graft versus host disease, fixed drug reactions, and multiple
others.
& 2017 Elsevier Inc. All rights reserved.

Introduction papules and plaques with a violaceous appearance with a pre-

dilection for the flexor surfaces of the trunk, thighs and genital
The terms ‘lichenoid’ and ‘interface’ dermatitis are often used areas (Fig. 1). The lesions are intensely pruritic, and frequently
interchangeably to describe an inflammatory pattern character- have fine white lines across them, also referred to as Wickham's
ized histologically by damage to the basal keratinocytes in the striae. Oral lesions are very frequent, and sometimes can be
epidermis.1,2 The mechanism of cell damage of such cells is now the sole manifestation of the disease.6 In rare occasions the mu-
best understood as apoptosis, or programmed cell death.3 The cosal surface of the esophagus can be involved.8–10 The lesions
apoptotic cells in the epidermis are also referred to as ‘Civatte typically last for approximately 12 months, before showing spon-
bodies’, and the ones in the dermis as ‘colloid bodies’.4 Another taneous resolution, the latter associated with post-inflammatory
frequent characteristic of this group of disorders is the presence of hyperpigmentation. While LP can be associated with a variety
vacuolar degeneration of the basal keratinocytes. As consequence of diseases (autoimmune11–13, immunodeficiency states14,
of such changes, there is variable melanin pigment incontinence in malignancy15,16, etc.), the most notorious association is linked to
the dermis because of the transfer of the pigment from the kera- the infection with HCV virus.17–19 Indeed, most patients should be
tinocytes. This inflammatory pattern of dermatoses, is also ac- screened for HCV infection upon the diagnosis of LP.
companied frequently by a band of lymphocytes and histiocytes in LP represents a model of what lichenoid and interface dermati-
the superficial dermis, that often obscures the dermal-epidermal tides are.2,7,20,21 In LP the epidermis is often times acanthotic, with a
somewhat irregular pattern of elongation of the rete ridges (Fig. 1).
junction, hence the term ‘lichenoid’. A discussion of the more
Such irregular pattern, often adopts a ‘sawtooth’ configuration. The
common lichenoid/interface dermatitides encountered in the
granular cell layer is often more cellular, and has a wedge-shaped
routine clinical practice is followed thereafter.
configuration. There is basal cell damage of the keratinocytes with the
presence of multiple apoptotic cells, Civatte bodies, and eosinophilic
colloid bodies in the dermis. Vacuolar degeneration of the basal ker-
Lichen planus and variants atinocytes is visible, and there is typically a ‘lichenoid’ band of lym-
phocytes and histiocytes that obscures the dermal-epidermal junc-
Lichen planus (LP) is a lichenoid and interface dermatosis of tion. Eosinophils are not typically seen, but are more frequent in the
unknown etiology.5–7 The clinical lesions appear as flat-topped hypertrophic forms of LP. Occasional plasma cells can be present,
particularly when located in mucosal sites.22 When the vacuolar
n
Correspondence to: University of Virginia Hospital, Room 3024, 1215 Lee St,
changes are very prominent, a cleft between the epidermis and der-
Charlottesville, VA 22908-0214, United States. mis forms, which is often referred to as ‘Caspary-Joseph spaces’. The
E-mail address: [email protected] (A.A. Gru). older the lesion is, the more frequent pigment incontinence is noted.

http://dx.doi.org/10.1053/j.semdp.2017.03.001
0740-2570/& 2017 Elsevier Inc. All rights reserved.
238 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249

Fig. 1. Lichen planus. Flat topped papules with a violaceous appearance on the ankle. The epidermis is acanthotic with hyperkeratosis on the surface. The acanthosis is
irregular and has a saw-tooth appearance. Areas of wedge-shaped hypergranulosis are present. The lichenoid and interface changes are illustrated by the presence of ‘civatte
bodies’ (apoptotic cells). A lichenoid band of lymphocytes and histiocytes is also present.

In atrophic lichen planus23–25, the epidermis is thinned and characterized, as the name implies, by epidermal hyperplasia with
there is loss of the normal rete pattern. The degree of inflamma- marked hyperkeratosis. Changes of lichen simplex chronicus are
tion is also less prominent than typical lesions of LP. Changes of often admixed with HLP. It is also important to be careful when
atrophic LP can clinically resemble porokeratosis. In hypertrophic diagnosing a squamous cell carcinoma on a superficial shave
lichen planus (HLP), the lesions are more typically described as biopsy of a patient with long-standing history of LP, as the treat-
plaques on the lower extremities, and sometimes have a verrucous ment is widely different.
appearance. Hypertrophic changes occur in long-standing lesions Annular lichen planus is more of a clinical, rather than a his-
of LP. The association between HLP and viral infections (HIV, HCV) tologic diagnosis.32 This is a rare variant of LP with lesions pre-
is higher than classic LP lesions.26,27 The other important feature to senting in the axilla, penis, extremities and groin, where clinically
remember of HLP is the higher predisposition to develop squa- resembles lesions of morphea, mycosis fungoides or gyrate er-
mous cell carcinoma and keratoacanthomas of the skin, similarly tythemas. Similarly, linear lichen planus shows a distinctive dis-
to what occurs in hypertrophic lupus erythematosus.28–31 HLP is tribution along the lines of Blaschko, and many of these cases can

Fig. 2. Oral lichen planus. The presence of white linear striae are seen in the mucosal cheek (2a). The oral mucosa is acanthotic, hyperkeratotic and shows a lichenoid band
(2b, 40x). This interface and lichenoid mucositis has scattered plasma cells in the infiltrate. Note the absence of the hypergranulosis that is frequently seen in the skin (2c and
2d, 100x and 200x).
 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249 239

also be classified as acute blaschkitis.33,34 Ulcerative or erosive LP, Histologically, LPP and FFA are identical, and the findings are
shows a characteristic predilection for the feet and genital sites. different depending on the duration of the lesion.53 There is a
This clinical variant has a much higher likelihood for development lichenoid reaction involving the basal layer of the follicular
of squamous cell carcinoma.35,36 Oral LP (Fig. 2) is present in 0.5– epithelium composed of lymphocytes and histiocytes. The
2% of middle-age to older individuals, and has a female pre- changes involve typically the more superficial portions of the
dominance. As opposed to ordinary LP, the lesions do not have hair follicle (infundibulum and isthmus) as opposed to lupus
spontaneous resolution. Histologically, the lesions lack the chan- erythematosus. Additionally, often the interfollicular epidermis
ges present in the granular cell layer. The degree of inflammation lacks the changes of LP, and there is perifollicular fibrosis and
is much heavier than classic LP, and plasma cells are abundant. perifollicular mucin.45,46,54 In counterpart, the cicatricial forms
Additionally, apoptotic keratinocytes are present at much higher of discoid lupus that can produce alopecia, show a deeper in-
levels than ordinary LP.6,37,38 flammatory infiltrate, there is an accompanying increased
Erythema dyschromicum perstans (EDP) (lichen planus pig- amount of interstitial dermal mucin, peri-eccrine inflammation,
mentosus, ashy dermatosis) represents a group of disorders that interfollicular epidermal interface changes, and clusters of
occur more frequently in individuals from certain areas of Latin plasmacytoid dendritic cells by CD123, which are helpful to se-
America (Mexico, Caribbean) and India, and manifested clinically parate apart both processes.55 In all scarring alopecias, loss of
as a progressive, slow-growing eruption with an ‘ashy’ appearance the sebaceous glands and piloerector muscles are noted. Once a
or brown macular hyperpigmentation.39–41 The lesions are more hair follicle is lost, an elastic stain can typically reveal a wedge-
often located in the trunk and upper extremities.42,43 Because shaped loss in vertical sections of LPP biopsies.
these lesions occur with higher frequency in patients with LP, EDP Lichen planus pemphigoides is an extraordinary rare disease
is now recognized as a macular form of LP. In some cases the as- that combines clinical findings of the vesiculo-bullous disorder
sociation between EDP and the use of paraphenylendiamine and bullous pemphigoid – BP (tense bullae in the extremities), with
aminopenicillins has been established.44 In the active phase of the mixed histologic findings of BP and LP, presence of dermal eosi-
disease, a lichenoid tissue reaction like LP is noted. However, the nophils, association with medications (ACE inhibitors, statins, an-
degree of inflammation is much milder than classic LP, and can tibiotics, etc) and specific direct immunofluorescence findings.56–
60
have a deeper dermal extension. The most notorious finding is the Patients with this disease, develop circulating auto-antibodies
degree of pigmentary incontinence in the dermis, frequently in the against the BP180 antigen (characteristic of BP). Histologically the
absence of interface changes. blisters are subepidermal, and contain abundant inflammatory
Lichen planopilaris (LPP) is a variant of LP characterized as a cells including neutrophils, eosinophils and lymphocytes. The non-
chronic form of scarring (cicatricial) alopecia that more fre- bullous lesions show all the features of classic LP accompanied by
quently occur in women (Fig. 3).45–48 It is the most common several eosinophils. Direct immunofluorescence shows linear de-
form of scarring alopecia (representing 1.15–7.59% of patients posits of C3 and IgG along the basement membrane zone.
seen in alopecia clinics). The lesions of LPP are manifested The differential diagnosis of LP is often with lupus er-
clinically as patches of hair loss with perifollicular erythema, ythematosus. As opposed to LP, in LE the epidermis is more fre-
scaling, and absence of follicular ostia. Approximately 17–50% of quently atrophic, there is thickening of the basement membrane
patients with LPP have other cutaneous lesions compatible with zone (more typical with older lesions), and there is a both super-
LP, and 25% of patients with LP have lesions of LPP. It's also im- ficial and deep perivascular and peri-eccrine inflammation ac-
portant to remember that changes of LPP are not only limited to companied by increased interstitial dermal mucin (a feature that
the scalp, and can occur in other sites (eyebrushes, etc). The so- can be demonstrated with Alcian blue or colloidal iron stains).
called frontal fibrosing alopecia (FFA) is a form of LPP where the Clusters of plasmacytoid dendritic cells (CD123þ) are also char-
clinical lesions are more limited to the frontal and temporal acteristic of LE, but not of LP.61–63 DIF can also help establish a
hairline, and associated with loss of the eyebrows.49–52 lupus band in LE. Hypertrophic LP can potentially mimic squamous

Fig. 3. Lichen planopilaris. Patches of hair loss with scarring are noted. There is slight perifollicular erythema and scaling. In LPP there is perifollicular fibrosis, typical of a
scarring alopecia. Note the interface changes along the hair follicle epithelium, with mild perifollicular inflammation, and absence of interface changes in the surface
epidermis.
240 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249

cell carcinoma; but the degree of atypia and architecture of the lichen striatus, but the degree of spongiosis appear to be more
lesion can usually help to discriminate between the two condi- prominent in the former.
tions. Other diagnostic challenges include lichenoid keratosis and
lichenoid drug reactions. Lichenoid actinic keratosis typically lacks
other features of LP and shows a significant degree of cytologic Lichen planus-like keratosis – LPLK (benign lichenoid
atypia of the cells. In the early lesions of lichen sclerosus (LSEA), keratosis)
interface and lichenoid changes occur. However, LSEA lacks the
irregular acanthosis, is accompanied by superficial homogeniza- This is one of the most common diagnosis made in the routine
tion of the collagen in the dermis, edema, and has loss of elastic dermatopathology practice.73–75 LPLKs are frequent solitary, dis-
fibers (features not typical of LP). Erythema multiforme and fixed crete, raised, erythematous lesions that have a clinical resem-
drug reactions have a much more rapid onset. Therefore, the le- blance to basal cell carcinomas. They are frequently located in the
sions can usually be distinguished clinically. In addition, both en- trunk or upper extremities of middle age to older individuals.
tities lack the changes in thickness of the epidermis and have Many authors (and recent molecular developments) believe that
apoptotic cells at all levels. LPLKs are examples of regressing benign epidermal neoplasms,
such as solar lentigines or seborrheic keratoses.76,77
Histopathologically LPLKs are characterized by florid tissue
Lichen nitidus reactions with or without pigmentary incontinence (Fig. 6). There
is both a lichenoid and interface process with apoptotic kerati-
This is a benign and self-limited dermatosis of children, char- nocytes at all levels of the epidermis, and inflammation obscuring
acterized by very small, 1–2 mm, flesh-colored papules with a the dermal-epidermal junction.73,78 It is important to remember
predilection for the upper extremities, trunk, and genitalia.64–67 that lichenoid reactions can sometimes obscure other neoplasms,
Histologically, the lesions of lichen nitidus are localized lichenoid particularly melanocytic lesions, and an adequate morphologic
reactions that are limited to 2–3 dermal papillae. The sharply de- evaluation sometimes should include immunohistochemical stains
marcated character of the infiltrate with the elongation of the rete to better highlight melanocytic nests.79,80 Additionally, one of the
at the edges in a ‘claw-like’ configuration is very characteristic of common mis-interpretations in the routine practice is to confuse
the disease (Fig. 4). The lichenoid inflammation is composed of LPLKs with cutaneous lymphomas.81,82 One should remember that
lymphocytes, histiocytes and pigmented melanophages. Foci of interface changes are quite unusual in the setting of mycosis
granulomatous inflammation are also common.65 fungoides (the most common cutaneous lymphoma), and the
unilesional forms of the disease are very rare. Some LPLKs can
have exuberant atypia of the lymphocytes, and even an abnormal
Lichen striatus phenotype. Some consider such lesions as examples of ‘lympho-
matoid keratosis’.82,83
Lichen striatus is also a self-limiting dermatosis with a pre-
dilection for children, that often presents within one side of the
body, usually within the length of an extremity.34,68–72 The lesions Fixed drug reactions
show a linear configuration, a papular appearance, and follow the
lines of Blaschko. Nail changes are also frequent. The histologic Fixe drug eruptions (FDE) develop within hours of taking the
changes are like those of LP, but more limited to 3–5 dermal pa- drug and recur at the same site with subsequent exposure to the
pillae. In addition, clusters of Langerhans cells in the epidermis, medication.84,85 The lesions can be solitary or multiple, typically
and apoptotic keratinocytes along all the layers of the epidermis oval or round, are in the face, lips, buttocks and genitals, and leave a
are seen. The most characteristic finding of lichen striatus is the hyperpigmented macule/s upon resolution (Fig. 7). The lesions can
peri-eccrine lymphocytic inflammation (Fig. 5). Mild spongiosis is also be bullous in nature.86–88 An innumerable number of medica-
also present. Adult blaschkitis can show significant overlap with tions can cause FDE: the most common agents linked to

Fig. 4. Lichen nitidus. Multiple flesh-colored flat very small (1–2 mm) papules are present in the forehead and nose of this young kid. Lichen nitidus histologically shows a
very small and well-defined area of lichenoid / interface changes that is limited to 2–3 dermal papillae. Note the presence of rare multinucleated giant cells in the infiltrate.
 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249 241

Fig. 5. Lichen Striatus. An interface/lichenoid dermatitis with mild epidermal acanthosis is noted (5a, 20x). The dermal-epidermal junction is blurred by the lichenoid
infiltrate (5b, 100x). A perieccrine lymphocytic inflammation is present (5c, 200x).

the differential diagnosis of FDE, erythema multiforme (EM) can

often be challenging to differentiate. While a solitary lesion that
recurs upon exposure to a medication can be easy to diagnose as
an FDE, cases with widespread disseminated lesions can be more
difficult. The pattern of inflammation is deeper in EM, the neu-
trophils are less common, and the vesiculation (if present) is
subepidermal (not intraepidermal).

Erythema multiforme/Steven-Johnson Syndrome/Toxic epi-

dermal necrolysis (EM/SJS/TEN)

These entities share similar clinical findings and are viewed, by

many, as a spectrum of interface dermatoses that range from a
milder disease (erythema multiforme) to a more aggressive sys-
temic process that can have associated multi-organ failure and is
the most common and severe dermatologic emergency in the
routine clinical practice (Steven-Johnson syndrome / Toxic epi-
dermal necrolysis).109–112 Because of the spectrum of clinical and
histopathologic manifestations, they will be described together.
EM is a self-limited, sometimes episodic disorder that can be
accompanied by oral involvement. The lesions are clinically pleo-
Fig. 6. Lichen planus-like keratosis. This is a solitary lesion very frequently con-
morphic and range from macules, papules, urticarial plaques, ve-
fused clinically with a basal cell carcinoma. A localized lichenoid infiltrate is noted
without significant cytologic atypia of the basal keratinocytes. sicles and bullae. The lesions often have a targetoid appearance
(Fig. 8). The two most common clinical forms are recurrent EM and
them include antibiotics (trimethoprim-sulfamethoxazole,8990 a rare form of persistent disease.110,112,113 The latter is associated
minocycline,91 nystatin,92 penicillin,93 amoxicillin,94 erythromycin,95 with underlying malignancies and EBV infection.114,115 The former
ciprofloxacin,96 antimalarials, anti-tuberculosis agents,97) analgesics is characteristically linked to different infectious agents, particu-
(colchicine,98 acetylsalicylic acid,99,100 acetaminophen,99,100 larly HSV virus.116–120 HSV-1 is classically associated with milder
naproxen, 101102
ibuprofen), antihistamines (diphenhydramine,103) forms of EM, whereas Mycoplasma pneumoniae121,122 infection
anticonvulsants (phenytoin,104 lamotrigine,105 carbamazepine,106 etc) and medications are linked to more aggressive forms. Other in-
and numerous others. fectious agents linked to the pathogenesis of EM include CMV,
In FDE there is an interface and lichenoid reaction with a very lyme disease, syphilis, molluscum, Chlamydia pneumoniae, HBV
dense inflammatory infiltrate that obscures the dermal-epidermal and others.113,123–126 The classic examples of medications asso-
junction (Fig. 7).107,108 Apoptotic keratinocytes at all levels of the ciated with EM include sulfonamides and NSAIDs.127–130
epidermis are present, in the absence of significant changes in TEN and SJS are on the severe spectrum end of EM. There is
thickness. The presence of spongiosis and intraepidermal vesicu- generalized erythema that progresses rapidly to blistering and
lation are also frequent, in addition to superficial dermal edema. extensive shedding of the skin. Indeed, patients with TEN are
The inflammation is more mixed: in addition to lymphocytes and treated similarly to individuals with severe and extensive burning.
histiocytes, neutrophils and occasional eosinophils are present. Erosive mucosal ulceration is also present. The mortality of TEN
The older lesions show an abundance of pigmented histiocytes. In can be as high as 35%. Most clinicians now divide SJS and TEN
242 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249

Fig. 7. Fixed drug reaction. Fixed drug reactions recur at the same site with subsequent exposure to the medication, and are typically macules with hyperpigmentation (7a).
A subtle interface dermatitis is noted, with discernible pigment incontinence in the dermis (7b and 7c, 40x and 100x). The interface changes are best demonstrated by
apoptotic cells at all levels of the epidermis (7d and 7e, 200x and 400x). A mild degree of spongiosis is present, a helpful clue to fixed drug reactions. A closer magnification
reveals the melanin pigment incontinence in the dermis and scattered eosinophils (7f, 400x).

according to the extent of cutaneous involvement, where SJS re- eosinophils. Severe lesions show overlap with SJS. In TEN, trans-
present cases with o10% of body surface involvement, and TEN epidermal necrosis and non-inflammatory bullae form, in addition
encompasses those with more than 30% skin affection. Medica- to the interface changes. A superficial inflammatory infiltrate is
tions are typically linked to both disorders, and particularly sulfas, noted, which if prominent might harbor a worse prognosis.
anticonvulsants (lamotrigine), anti-depressants and NSAIDS.130–132 The differential diagnosis is broad, and often includes many
Histologically, there is a lichenoid (interface) reaction which blistering disorders. Because of the lack of immunoreactants by
often obscures the dermal-epidermal junction. There is very pro- direct immunofluorescence, other blistering diseases can be easily
minent apoptosis, and typically at all levels of the epidermis distinguished from EM/TEN. The distinction with fixed drugs has
(Fig. 8). Vacuolar alteration of basal keratinocytes and mild spon- been previously discussed. Graft versus host disease (GVHD) can
giosis can also be seen.133–135 The presence of interface changes sometimes be challenging. Nonetheless, the history of bone mar-
accentuated in the acrosyringeal structures has been linked as a row transplant (and rarely solid transplant recipients) can be
finding more typically associated with medications (the latter also helpful. Additionally, the higher grades of GVHD (3 or 4) which can
associated with few scattered dermal eosinophils).136 When the present with blisters or necrosis are extraordinary rare in the
interface changes evolve, subepidermal blisters form that typically current times. Pityriasis lichenoides et varioliformis acuta (PLEVA)
lack significant inflammatory cells within. The lichenoid infiltrate can also present with prominent interface changes and epidermal
is composed largely of lymphocytes and histiocytes, with scattered necrosis. However, a distinctive feature of PLEVA represents the

Fig. 8. Erythema multiforme. Characteristic targetoid lesions of EM. Prominent interface changes with frequent clusters of keratinocyte necrosis, atrophy of the epidermis.
There is early formation of a subepidermal cleft.
 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249 243

presence of a small-vessel vasculitis. Additionally, the chronology grade 2 is characterized by apoptotic cells in the epidermis and/or
and character of the lesions is different from EM. Epidermal ne- follicle, in addition to a dermal lymphocytic infiltrate; grade 3 le-
crosis can be caused by ischemia, and more notably in the setting sions have fusion of basilar vacuoles along the dermal-epidermal
of a thrombotic vasculopathy. Fibrin thrombi are not typical on junction to show small clefts and microvesicles; grade 4 shows
cases of TEN/SJS. TEN should also be distinguished from staphy- complete separation of the epidermis from the dermis and/or
lococcal scalded skin syndrome (SSSS). As opposed to TEN, SSS epidermal necrosis. Most biopsies of aGVHD fall under grade 2 or
shows only superficial necrosis, is more typically seen in children, 3 lesions. An under recognized histologic phenomenon in most
and has a much better prognosis. biopsies of acute GVHD is the presence of dysmaturation of the
keratinocytes, that often mimics the changes seen in actinic
keratosis.156 The latter appears to be attributed to the damaging
Graft versus host disease (GVHD) effects of the chemotherapeutic agents used for conditioning in
the transplant recipient. Chronic GVHD has 2 characteristic pat-
Graft versus host disease is a systemic process with frequent terns: an earlier phase that histologically resembles lichen planus
cutaneous manifestations, that leads to a significant morbidity and (irregular epidermal acanthosis, interface and lichenoid changes),
mortality in patients with a history of bone marrow transplanta- and a later fibrosing phase that shows the features of systemic
tion (BMT).137–141 Acute GVHD occurs in 1/3 of patients following scleroderma.154,157–159 The classic sclerodermoid cGVHD shows
allogeneic BMT.138,142–145 Some of the risk factors associated with mild epidermal atrophy and subtle vacuolar alteration of the basal
an increased incidence of GVHD include history of chronic mye- keratinocytes. There is dermal fibrosis with thickening of the
logenous leukemia, HLA mismatch and total body irradiation.146 It collagen bundles and atrophy of the adnexal structures. The fi-
can be rarely observed following solid organ transplants.147,148 brosis extends to the deep portions of the adipose tissue. Some-
Individuals who receive stem cell or cord blood transplant less times coexistent changes of acute and chronic GVHD are noted.
frequently develop GVHD. In the differential diagnosis of GVHD the most notable and
The acute phase of the disease is associated with GI symptoms problematic category is a drug hypersensitivity reaction. During
(vomiting, diarrhea), elevation of liver transaminases and a skin the first three weeks after transplant, the distinction between
rash. The rash is characterized by erythematous macular lesions GVHD and a drug eruption is sometimes impossible. Eosinophils,
that are generalized.138 Sometimes the lesions can show a more while rare, can sometimes be seen in GVHD. Fulminant lesions
notorious accentuation in flexural sites, have a papular or blister- with transepidermal necrosis resemble TEN. The so-called erup-
ing configuration, or have features of TEN.149 The chronic phase tion of lymphocyte recovery occurs during the first 3–4 weeks’
of GVHD, which carries significant morbidity, typically occurs post-transplant and show identical features to aGVHD. The chronic
several months after the diagnosis of acute GVHD; approximately GVHD lesions resemble lichen planus in the early stages, and
80% of patients with chronic GVHD (cGVHD) had an acute morphea or systemic sclerodermal in the fibrosis phase.
phase.143–145,150–154 Early on, cGVHD resembles lichen planus
clinically (including the presence of oral lesions). This is followed
by a poikilodermatous phase, which later transforms into a fi- Lupus erythematosus and variants
brosing sclerodermoid phase, that mimics clinically and histolo-
gically systemic scleroderma. Lupus erythematosus (LE) is a chronic connective tissue dis-
Acute GVHD is a lichenoid dermatitis. A grading system has order that is associated with the formation of autoantibodies.
been proposed by Horn et al.155, and is widely used in the clinical Three main forms are noted, all of which show frequent cutaneous
practice. This grading system is divided in four (Fig. 9): grade involvement: a pure cutaneous variant, discoid LE (DLE); a sys-
1 lesions show mild vacuolar alteration of the basal keratinocytes; temic form (SLE) with cutaneous and systemic manifestations; and

Fig. 9. Graft versus host disease (GVHD). In grade 1 lesions, there is minimal vacuolar changes of the basal keratinocytes. Epidermal atrophy is also seen (9a and 9b, 40x and
200x). In grade 2 lesions, apoptotic keratinocytes are present. Dysmaturation of the individual keratinocytes mimicking the changes of actinic keratosis is present (9c and 9d,
200x and 400x).
244 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249

Fig. 10. Discoid lupus erythematosus. Lesions with a ‘butterfly’ pattern on the face are present. In discoid lupus, a superficial and deep, perivascular and periadnexal
lymphocytic infiltrate is noted, accompanied by follicular plugging.

a milder systemic form, subacute LE.160–162 Some variants of LE can lesions have marked hyperkeratosis and acanthosis.188 Transepi-
lack significant interface changes in the biopsies: those include dermal elimination of elastic fibers can occur. Using direct im-
tumid LE and lupus panniculitis. The so-called ‘Jessner's lympho- munofluorescence, a lupus band (IgG and IgM) deposits along the
cytic infiltrate’ is now believed to be a synonym for tumid LE.163– basement membrane zone in 50–90% of cases.189–192
165
In the recent years, many cases of lupus panniculitis have been
reported in association with a form of primary cutaneous T-cell Subacute lupus erythematosus (SCLE)
lymphoma, subcutaneous panniculitis-like T-cell lymphoma
(SPTCL).166,167 Some believe that lupus panniculitis and SPTCL are The clinical lesions in subacute lupus erythematosus (SCLE) are
in the spectrum of an autoimmune disorder that can progress to a composed of non-scarring papulosquamous or annular lesions that
T-cell dyscrasia.168,169 are widely distributed on the face, neck, upper trunk and arms
(Fig. 11).193–196 Many of SCLE patients have mild systemic symp-
Discoid lupus erythematosus toms, including musculoskeletal and serologic abnormalities.197,198
The kidneys are affected in 16% of patients.199 Many medications
DLE is characterized by erythematous annular plaques with a are associated with development of SCLE: some of the common
sharply defined border and follicular plugging (Fig. 10). The lesions examples of them include TNF inhibitors (infliximab200,
are classically distributed in the face and have a ‘butterfly’ dis- etanercept201, adalimumab202), antidepressants (bupropion203,
tribution (cheeks and nose bridge).170–175 The neck, scalp and oral citalopram204), anticonvulsants (phenytoin205), statins206,
mucosa can also be affected. The lesions typically undergo atrophy antihistamines207, calcium channel blockers 208, proton pump in-
and scarring. Indeed, DLE can present as a form of scarring hibitors (omeprazole, lansoprazole, esomeprazole)209,210, anti-
alopecia.45,176,177 Verrucous and hypetrophic lesions can rarely biotics (doxycycline)211, systemic chemotherapeutic agents 212, etc.
develop and, in those circumstances, a diagnosis of squamous cell ANA serology is typically positive, which can also be accompanied
carcinoma should be considered.178,179 Face and arms are the most by Ro/SSA antibodies.
common sites of hypertrophic DLE. Clinical and histologic overlap Histologically SCLE is milder than DLE and lacks the follicular
between DLE and EM can sometimes occur and such variant is also plugging noted on the latter.160,187,213–215 The biopsies of SCLE have
referred to as Rowell syndrome.180,181 The latter frequently has a more vacuolar alteration of the basal keratinocytes, epidermal
positive rheumatoid factor and a speckled pattern of antinuclear atrophy, dermal edema and mucin when compared to DLE
antibodies (ANA). It's also important to note that DLE lesions are (Fig. 11). The inflammation is also more superficial in SCLE com-
seen in 20% of cases of SLE.182 It's believed that approximately 5– pared to DLE. The papulosquamous lesions have no distinctive
10% of DLE can progress to SLE.183–185 Most patients with classic features to distinguish from DLE. A pattern of TEN-like findings
DLE lack ANA. can sometimes be seen in SCLE. The lupus band is noted in 60% of
DLE shows both an interface and lichenoid dermatitis with a cases. A speckled pattern (dust-like particles) has been described
superficial and deep dermal lymphocytic inflammatory infiltrate among the basal keratinocytes, and is associated with the presence
that has a both perivascular and periadnexal distribution of Ro/SSA antibodies.216,217
(Fig. 10).160,186 Follicular plugging is typical. The inflammation
around the hair follicles is more evident at the level of the mid- Systemic lupus erythematosus
portions. Older lesions are frequently accompanied by thickening
of the basement membrane zone, a feature that can be highlighted SLE is a systemic connective tissue disorder with frequent cu-
by a PAS stain. The inflammation is composed of small lympho- taneous manifestations.162 There are 4 major sites typically in-
cytes, histiocytes and scattered plasma cells. Eosinophils are not volved in the disease: skin, joints, kidneys and serosal surfaces.
typical, except for the more hypertrophic lesions. Interstitial der- The cutaneous lesions are characterized by erythematous, in-
mal mucin is increased, a finding that can be proven using col- durated patches with slight scaling in the malar areas. As opposed
loidal iron or alcian blue stains. In some cases, a small-vessel to DLE, the lesions are more extensive, less defined and lack
vasculitis can be demonstrated superficially.187 The hypertrophic atrophy. Other types of skin manifestations include urticarial,
 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249 245

Fig. 11. Subacute lupus erythematosus. Papular lesions and annular plaques are present on the face. Epidermal atrophy, more prominent vacuolar alteration of the basal
keratinocytes, edema and interstitial dermal mucin are present (the latter is highlighted by a colloidal iron stain).

bullous, follicular, mucinous, purpuric or urticarial lesions. 20% of Neonatal lupus erythematosus
SLE patients lack skin manifestations.218 In childblain lupus (lupus
pernio), there is involvement of the acral sites.219,220 Other auto- Neonatal LE is a rare variant of the disease that presents as a
immune disorders can present in association with SLE. One im- transient, self-limiting, dermatitis accompanied frequently by
portant association should be highlighted with Kikuchi's disease congenital heart block and hematologic alterations. The cutaneous
(necrotizing histiocytic lymphadenitis).221 Such patients are more lesions resemble subacute LE. Lesions in the scalp, periorbital and
prone to develop SLE. An important part of the diagnosis of SLE in the extremities, are common. Occasionally the lesions resemble
involves the evaluation of circulating autoantibodies: most pa- those of Langerhans cell histiocytosis. Approximately 20% of
pregnant women with SLE will subsequently develop neonatal LE.
tients have ANA antibodies. Approximately 50% of SLE patients
The Ro/SSA antibody is present in the infants in nearly all
have antibodies to double-stranded DNA (dsDNA), a finding that is
cases.223–226 The histopathologic changes are identical to those of
linked to renal disease (and can help monitor the disease activity
subacute LE, previously described in this article.
along with C3 complement levels). Other antibodies that can be
identify include extractable nuclear antigen (ENA) and Ro60. An- Bullous lupus erythematosus
tineutrophilic cytoplasmic antibodies (ANCA) are seen in many
cases of minocycline-induced lupus-like syndrome and isolated Bullous LE is a skin eruption that resembles clinically and
SLE.222 histologically dermatitis herpetiformis. The blisters have a
In SLE there is vacuolar damage to the basal keratinocytes but subepidermal location, and contain a rich number of neu-
without significant Civatte body formation.160,162,174,175,182 A su- trophils. Papillary dermal neutrophilic micro abscesses are also
perficial lymphocytic inflammatory infiltrate is noted, with seen. Marked leukocytoclasis around superficial dermal vessels
sometimes evidence of a small-vessel vasculitis. The presence of are seen. The interface changes seen in other forms of LE are
eosinophils suggests the possibility of drug-induced SLE. Thick- not present in bullous LE. DIF shows linear / granular deposits
ening of the basement membrane and increased dermal mucin can of IgG, and sometimes IgA and IgM along the basement
be proven with special stains. In lupus pernio, a lymphocytic membrane zone. 227–230
vasculitis accompanied by superficial edema and red blood cell
extravasation is present. By direct immunofluorescence reactants
are present in nearly 100% of the skin biopsies. Similarly, to kidney Dermatomyositis
biopsies, all immunoglobulins (IgG, IgM, IgA) and complement can
be present. Nuclear staining for IgG in the epidermis is present in a This form of connective tissue disorder characteristically pre-
sents with inflammation of the skeletal muscle and skin.231–236 The
small proportion of cases and correlates with oral involvement.
cutaneous lesions can precede the myositis by up to 2 years or
A major differential diagnosis for all variants of LE is LP. As
more, and cases of isolated cutaneous involvement (amyopathic
opposed to most forms of LE, LP has irregular epidermal acanthosis
dermatomyositis) are frequently encountered.237–239 The latter form
with hypergranulosis and a ‘sawtooth’ appearance of the rete
represents 10–20% of cases of dermatomyositis (DM) in the US. DM
ridges. Additionally, a band-like infiltrate that obscures the der-
can occur at any age; cases presenting during childhood (juvenile
mal-epidermal junction is present. The deep dermal inflammation DM) have a higher prevalence of systemic involvement.240,241
and presence of interstitial mucin is also an unusual finding of LP. Clinically, DM presents with violaceous or erythematous scaly
In LPP, focal follicular plugging can be present in the biopsies. lesions with a predilection for the face, shoulders, forearms and
More recently, clusters of plasmacytoid dendritic cells (identifiable thighs (Fig. 12). A poikilodermatous pattern (atrophy, telangiecta-
by CD123) are typical of LE, but not of LP. DIF can also be helpful sia, and hyperpigmentation) can also occur. Some lesions can
when demonstrating a lupus band. Finally, ANA are pathogno- adopt a ‘salt and pepper-like’ appearance. Other cutaneous mani-
monic of LE at very high titers (in the subacute LE and SLE, but not festations include nail fold changes, gingival telangiectasis, pur-
DLE). plish decoloration of the periorbital region (heliotrope rash), and
 246 A.A. Gru, A.L. Salavaggione / Seminars in Diagnostic Pathology 34 (2017) 237–249

Fig. 12. Dermatomyositis. Erythematous and violaceous plaques on the face. Histologically, there is a lichenoid dermatitis with vacuolar changes of the keratinocytes, and
epidermal atrophy. Slight superficial vascular dilatation of the vessels in the dermis is found. This pattern resembles a poikiloderma.

papules or plaques over the knuckles (Gottron's papules). Other patients with suggestion of clinicopathologic diagnostic criteria and therapeutic im-
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