Inflammatory Diseases of the Skin
Moderator: Dr. Lorenzo Cerroni
Cases 1-3 -
Timothy McCalmont, MD
University of California, San Francisco
At the beginning of the 20th century, a diagnosis of dermatitis was fashioned largely by
clinical observation. The clinical pattern observed was matched to the patterns known to the mind of the
beholder, and a diagnosis was rendered based upon the closest fit, in the opinion of the observer. Many
dermatologists divided inflammatory conditions into "hyperemias," characterized by an "abnormal flux of
blood" with lesser inflammatory changes, and "inflammations," in which erythema might also be present but
in which inflammation was overt. The infectious nature of many conditions was poorly understood, and
thus there was not clear distinction between infectious cutaneous diseases and their strictly dermatitic
It was clear even to early dermatologists that many seemingly unrelated disorders were sometimes (or
perhaps often) indistinguishable, and microscopical examination of skin biopsies began to be utilized as
a means to obtain unique findings that would point to a specific diagnosis. In this first conception of
dermatopathology, the clinician and pathologist were usually the same individual. Only much later did
the present paradigm of an independent pathologist/dermatopathologist evolve.
Conceived by Wallace Clark and refined and disseminated by Bernard Ackerman, pattern analysis has
moved to the fore as the favored method for the classification and diagnosis of dermatitis, and
conventional microscopical assessment has also been utilized as a means to gain insight into the
pathogenic mechanisms that underlie these diseases. Now instead of erythemas and inflammations, we
ponder whether a dermatitis should be considered spongiotic or psoriasiform or vacuolar or lichenoid in
nature, and whether a blistering eruption shows intraepidermal or subepidermal vesiculation, and we
further wonder about the exact structural antigen that is associated with the eruption.
This discussion will briefly review insights into several diseases that are characterized by changes
involving the interface between the epidermis and dermis, a collection of inflammatory diseases known
simply as interface dermatitis. Interface dermatitides can be broadly characterized as vacuolar or lichenoid with respect to
their microscopical pattern, and as acute or chronic in nature.
Vacuolar interface dermatitis is characterized by vacuolar alteration of the lowermost epidermis,
generally in concert with a sparse or modest perijunctional infiltrate. Vacuolar alteration represents
keratinocytotoxic alteration of the epidermis by a cell-mediated lymphocytic attack. Vacuolar alteration
may be acute or chronic in nature (discussed immediately below). Lichenoid dermatitis is characterized
by a dense perijunctional infiltrate in association with vacuolar changes. Because of the density of the
perijunctional infiltrate, sometimes vacuolar alteration may be less obvious in a lichenoid process. It
is important to note that there is overlap between things vacuolar and things lichenoid. The purpose of
stratification of a process as vacuolar or lichenoid is merely to enable an algorithmic approach to
differential diagnosis to be applied.
Generally, the determination as to whether an interface eruption is relatively acute or relatively
chronic can be made based upon histopathological parameters, without exact reference to the clinical
situation. An acute eruption is typified by little alteration to the superjacent stratum corneum, as
well as an unaltered (non-fibrotic) papillary dermis. A chronic eruption is typified by overlying
hyperkeratosis and/or parakeratosis, as well as alteration of the epidermal thickness (with either
acanthosis or atrophy). Furthermore, the papillary dermis is typically expanded or altered by fibrosis
or sclerosis in association with a chronic interface eruption.
The categories of greatest value in algorithmic differential diagnosis include acute vacuolar
interface dermatitis, such as erythema multiforme, fixed drug reaction, or graft-versus-host disease;
chronic vacuolar interface dermatitis, such as discoid lupus erythematosus or dermatomyositis; and
(chronic) lichenoid dermatitis, such as lichen planus, lichen nitidus, lichen striatus, or a lichenoid
In the paragraphs that follow, 3 eruptions that serve as the basis for today's illustrative
presentation of interface dermatitis will be reviewed in greater detail.
Erythema Multiforme (EM)
In the distant past, erythema multiforme was (poorly) defined as an acute inflammatory disease
characterized by reddish macules, papules, or even "tubercles," which occasionally could become vesicular
or bullous and which varied in size and shape—i.e. were "multiform" in clinical character. The etiology
was commonly thought to be secondary to exposure to a toxin, perhaps derived from food. Clinical
patterns such as erythema iris, erythema annulare, and erythema bullosum were often interpreted as
variants within the broad and nebulous clinical spectrum accepted as EM.
Case 1: 68-year-old female with recurrent eruption 2-3 years, with recent flare of scattered tender to painful, bilateral and asymmetrical discrete, smooth tumid papules and patches (to several cm.) on torso, limbs, and fingers. She is on several medications; CBC normal, ESR-38 (one month ago); 5 mm punch at center of tender 1 1/2 cm disc right inner knee.
Case 1 - Slide 1
By the early 1960s, a clinical pattern characterized by extensive involvement of the mucous membranes
had been described by Stevens and Johnson. At that time, there was not a clear distinction between
bullous pemphigoid and EM, and the former was often considered a chronic variant of the latter.
Descriptions of microscopical findings were vague and included mention of spongiosis and intracellular
edema above a lymphocytic infiltrate, with variable mention of changes of "vasculitis." By the early
1970s, the confusing concept of "epidermal" and "dermal" and "mixed" patterns of EM was in play. Some
"dermal" examples of EM were probably misclassified examples of urticarial dermatitides, while others
were merely a reflection in the zonal variation in microscopical findings within EM lesions (depending
upon whether the central necrotic area or the edematous peripheral area of a lesion had been sampled).
By the mid to late 1970s, it was generally established that EM represented a type of dermatitis
characterized by "hydropic degeneration" or vacuolar change at the epidermal-dermal junctional zone.
At present, it is currently accepted that EM is an acute form of vacuolar interface dermatitis, that
Stevens-Johnson syndrome represents a clinical variant with pronounced mucosal involvement, and that
toxic epidermal necrolysis (TEN) represents EM with extensive, confluent epidermal necrosis. EM minor
refers to cases with limited cutaneous disease, typically presenting in papulovesicular fashion and
stereotypically presenting with targetoid lesions accentuated on the acra. EM major refers to cases with
extensive and/or mucosal involvement, including both Stevens-Johnson syndrome and TEN.
Histopathologically, EM presents with the pattern of an acute vacuolar interface dermatitis, with
vacuolar alteration at the junction below a normal or near-normal epidermis, and with a perijunctional
lymphocytic infiltrate that tends to be restricted to the superficial dermis and tends to be of only
modest density. Typically, the infiltrate in EM is strictly lymphocytic in composition. Admixed
eosinophils may be encountered, particularly in examples of drug-induced disease.
A link between herpes simplex labialis and recurrent EM had been observed clinically, and the
inception of antiviral therapy provided further evidence of a relationship when it was observed that
acyclovir treatment suppressed the subsequent development of EM lesions in such patients. Clinicians
refer to such cases as "herpes-associated EM" or HAEM. Subsequent analysis of paraffin-embedded tissue
after PCR expansion confirmed the presence of herpes simplex virus genomic DNA within many EM lesions,
and it is presumed that the cytotoxic (vacuolar) pattern represents a specific injury induced by
virally-altered keratinocytes. The majority of cases of EM are now thought to be secondary to herpes
virus infection, including some cases in which there is no clinical evidence of primary herpetic labialis
or genitalis (occult primary disease), and also including some cases with extensive mucosal disease
As alluded to above, EM can also be induced by medications, and the cause of some cases remains
unknown, despite clinical investigation.
Fixed drug reaction
Fixed drug reaction was originally introduced as a term by Brocq in 1894, after the development of an
erythematous pigmented localized eruption after the ingestion of antipyrine. By the 1970s it was well
documented that fixed drug reaction represented an interface dermatitis of vacuolar type that could be
identified microscopically on the basis of vacuolar interface change, necrosis of individual
keratinocytes, and a mixed infiltrate including granulocytes and admixed melanophages.
Case 2: 56-year-old male with 2 week pruritic, semi-annular eruption on trunk.
Case 2 - Slide 1
Clinically, the "fixed" nature of a fixed drug reaction stems from the fact that clinical lesions are
topographically fixed—lesions recur at exactly the same site when rechallenge with the causative
medication occurs. In the first occurrence of a fixed drug reaction, a stage undocumented (and perhaps
undocumentable) clinically, the presentation is as erythematous plaques. Just like erythema multiforme,
papulovesicular changes can be observed within lesional skin, and sometimes clear vesicular or bullous
changes will occur. With repetition, considerable post-inflammatory change occurs, which is unsurprising
given the restricted clinical distribution of the inflammatory insult. Thus, in repeat episodes, plaques
tend to assume a reddish-brown or even a violaceous hue. In some patients, the distribution of disease
will become somewhat greater with each "rechallenge" with the causative agent. Rarely, a generalized
fixed drug reaction (the "fixed" equivalent of TEN) can occur.
Histopathologically, the primary pattern of a fixed drug reaction is that of an acute vacuolar
interface dermatitis, with vacuolar alteration of the junctional zone below a relatively normal-appearing
basket-weave stratum corneum. The infiltrate tends to be substantial, relatively deep in distribution,
and clearly mixed, with eosinophils and/or neutrophils present near the junctional zone, and with
numerous melanophages present in the papillary dermis as well. Much like EM, striking vacuolar
alteration can eventuate with confluent necrosis and/or subepithelial vesiculation, yielding a bullous
microscopical pattern. Some examples of fixed drug reaction present with ballooning (intracellular
edema) of keratinocytes, creating a constellation that includes a viral vesicular dermatitis in the
Clinical and histopathological findings suggest that drug ingestion elicits cytotoxic destruction of
keratinocytes by lymphocytes, and presumably a drug-derived determinant expressed on the keratinocyte
surface provokes the process. Recent immunoperoxidase evidence indicates a cytokine-mediated
keratinocytotoxic process in which gamma interferon plays a role.
Lichen planus (and hypertrophic lichen planus)
In general, diseases that present with a lichenoid microscopical pattern represent chronic forms of
interface dermatitis. A number of different maladies can be considered in the differential diagnosis
when a lichenoid configuration is encountered, including lichen planus (LP), lichen striatus, and even
mycosis fungoides. LP, the prototypical lichenoid disorder, represents a relatively common disease with
highly variable findings. The diversity comes from a wide spectrum of clinical and histopathological
findings. Clinically, LP most common presents as small pruritic polygonal papules that are accentuated
on the acra or genitalia. Variant clinical forms include LP that presents with distinctive clinical
morphology, such as annular, atrophic, vesicular, or erosive LP, as well as LP that presents with
involvement restricted to a specific site, such as ungual LP or follicular LP (lichen planopilaris).
Case 3: 82-year-old female with 2 cm red nodule. "Consider SCC, BCC, or trauma"
Case 3 - Slide 1
Histopathologically, LP presents with a dense bandlike lymphocytic or lymphohistiocytic infiltrate
that is typically restricted to the papillary dermis. The afflicted epidermis shows a spectrum of
chronic alterations, including slight hyperplasia, hypergranulosis, and compact orthohyperkeratosis,
typically with little if any parakeratosis present. There is typically clear vacuolar change at the
junction; when pronounced, it may appear that the basal epidermis has been lost and that squamous
keratinocytes of the stratum spinosum are present abutting the dermis, a configuration known as
"squamotization" of the basal layer. Variant microscopical forms include atrophic lichen planus, in
which the epidermis is attenuated rather than amplified, and vesiculobullous LP, in which basal vacuolar
alteration is present to a degree that yields subepithelial separation.
Hypertrophic LP represents an important variation that is distinctive both clinically and
histopathologically. The clinical lesions are distinctive in that they present in nodular (rather than
papular) fashion and are often restricted to the lower extremities. The clinical lesions of hypertrophic
LP may lack associated pruritus. Histopathologically, the lesions of hypertrophic LP show the
characteristic vacuolar reaction, squamotization, and lichenoid infiltrate that would be expected in
association with conventional LP, but are distinctive for the concurrent presence of irregular epithelial
hyperplasia. In a sense, hypertrophic LP is merely conventional LP with concomitant pseudocarcinomatous
hyperplasia of the surface epithelium. Because of the pseudocarcinomatous alteration, lesions of
hypertrophic LP can be misconstrued as either squamous cell carcinoma or keratoacanthoma. This
challenging differential diagnosis is rendered even more difficult by the fact that keratoacanthomas and
carcinomas have been documented to arise within lesions of hypertrophic LP. In short, in the evaluation
of a potential case of hypertrophic LP, one should also consider the possibility of carcinoma or
keratoacanthoma in the differential diagnosis, including the possibility of a keratoacanthoma arising
within a lesion of hypertrophic lichen planus.
- Darragh TM; Egbert BM; Berger TG; Yen TS. Identification of herpes simplex virus DNA in lesions of erythema multiforme by the polymerase chain reaction. J Am Acad Dermatol,1991 Jan, 24(1):23-6.
- Brice SL; Leahy MA; Ong L; Krecji S; Stockert SS; Huff JC; Weston WL. Examination of non-involved skin, previously involved skin, and peripheral blood for herpes simplex virus DNA in patients with recurrent herpes-associated erythema multiforme. J Cut Pathol, 1994 Oct, 21(5):408-12.
- Aslanzadeh J; Helm KF; Espy MJ; Muller SA; Smith TF. Detection of HSV-specific DNA in biopsy tissue of patients with erythema multiforme by polymerase chain reaction. Br J Dermatol, 1992 Jan, 126(1):19-23.
- Molin L. Oral acyclovir prevents herpes simplex virus-associated erythema multiforme. Br J of Dermatol, 1987 Jan, 116(1):109-11.
- Orfanos CE, Schaumburg-Lever G, Lever WF. Dermal and epidermal types of erythema multiforme. Arch Dermatol, 1974, 109:682-88.
- Korkij W; Soltani K. Fixed drug eruption. A brief review. Archives of Dermatology, 1984 Apr, 120:520-4.
- Kossard S et al: Hypertrophic lichen planus-like reactions combined with infundibulocystic hyperplasia: pathway to neoplasia. Arch Dermatol. 2004 Oct;140(10):1262-7.
- Chave TA, Graham-Brown RA: Keratoacanthoma developing in hypertrophic lichen planus; Br J Dermatol. 2003 Mar;148(3):592.