Seminars in Diagnostic Pathology 34 (2017) 250-260

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Seminars in Diagnostic Pathology

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Bullous, pseudobullous, & pustular dermatoses

Mark R. Wick1
Section of Dermatopathology, Division of Surgical Pathology & Cytopathology, University of Virginia Medical Center, Charlotte sville, VA, United States

articleinfo abstract

Several dermatoses are typified by the formation of spaces (blisters; bullae) within or beneath the
Keywords: epidermis. These may be acellular or filled with particular species of inflammatory cells. Etiological ca-
Bullous skin diseases tegories include infectious, immune-mediated, genetic, drug-related, and idiopathic lesions. Examples of
Impetigo such disorders include impetigo, Herpes virus infections, pemphigus, bullous pemphigoid and pemphi -
Herpes infections goid gestationis, epidermolysis bullosa acquisita, IgA-related dermatoses, inherited epidermolysis bullosa
Pemphigus variants, Hailey-Hailey disease, and porphyria cutanea tarda. Other conditions manifest microscopic
Pemphigoid acantholysis within the surface epithelium but are not associated with clinical bullae, such as Dar ier
Epidermolysis bullosa acquisita
disease and Grover disease. Finally, both infectious and non-infectious causes exist for the development of
IgA-mediated dermatoses
neutrophilic pustules in the epidermis, as seen in pustular psoriasis, Sneddon -Wilkinson disease
Inherited epidermolysis bullosa
Hailey-Hailey disease (subcorneal pustular dermatosis), and acute generalized exanthematous pustulosis. This review con-
Cutaneous porphyria siders the clinical and histological features of all of these diseases.
Darier disease & 2017 Elsevier Inc. All rights reserved.
Grover disease
Pustular skin diseases

Because of their relative rarity and a regular requirement for ad-
junctive diagnostic studies, lesions with bullous features are regarded as
perplexing by many pathologists. Etiologic underpinnings for such
conditions include various genodermatoses, infections, inflammatory
dermatoses, drug reactions, and autoimmune blistering disorders. This
brief review aims to provide a practical approach to the interpretation of
vesicobullous cutaneous diseases.
Biopsies of vesicobullous clinical skin lesions
Dermatologists are trained to take at least 2 biopsy specimens
from cutaneous lesions that are vesicobullous. One is submitted for
histologic examination in formalin, and the other is placed in a
non-fixative transport medium (e.g., Michel's solution) or frozen in
liquid nitrogen. The second sample can then be studied by direct
immunofluorescence microscopy (DIFM) for the possible presence of
bound immunoglobulins and complement fractions. 1 That form of
analysis is not easily performed—if it can be done at all—using
formalin-fixed, paraffin-embedded tissue sections. 2
Non-dermatologists may not know of this routine. Accordingly,
when specimens from their patients show vesicobullous morphological
changes that may be autoimmune in nature, they should be prompted by
the pathologist to do additional biopsies for DIFM.
E-mail address: mrwick1@usa.net
1
Contact information—Dr. Wick, Room 3020 University of Virginia Hospital,
1215 Lee Street, Charlottesville, VA 22908-0214, United States.
Infectious vesicobullous disorders of the skin
Bacterial Infections
Selected bacterial cutaneous infections may cause vesicles and
bullae to form. Two of them—erysipleas and necrotizing fas-
ciitis—have been considered elsewhere in this issue of Seminars
and will not be covered here. Another important disease in this
category is bullous impetigo, a common condition in children
and adolescents.3 It is caused by mixed infections by Staphylo-
coccus aureus and Streptococcus pyogenes, but only rarely can
those organisms be demonstrated histologically within the
lesions.
Clinically, impetigo takes the form of multiple grouped ve-
sicles and bullae that contain yellowish fluid, usually on the face.
They easily rupture, and the resulting exposed reddish plaques of
tissue are then covered with crusts. Etiologically, impetigo is
often seen in children and teenage athletes who have skin-to-
skin contact with other individuals who carry the causal
bacteria.4
This histologic hallmark of impetigo is the presence of a sub-
corneal intraepidermal blister that is filled with neutrophils.3(Fig. 1).
Differential diagnosis is limited, practically represented only by
acute bullous cutaneous lupus erythematosus (a rare disorder).5
The clinical presentation typically allows for an easy distinction
between these conditions.

http://dx.doi.org/10.1053/j.semdp.2016.12.001
0740-2570/& 2017 Elsevier Inc. All rights reserved.
 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260 251

Fig. 1. Bullous impetigo is shown here. The bullae on this patient's face have ruptured, leaving scabs and open erosions (lef t). Histologically, the lesions are typified by
subcorneal blisters filled with neutrophils (right panels).

Viral infections—Herpesviridae
Herpes simplex and Varicella-zoster are both members of the
viral family Herpesviridae, and the clinical lesions that they pro-
duce are similar in appearance. Herpes is most often seen in the
facial skin or the oral and anogenital mucosa, although selected
cases—for example, those in which digital contact with an active
lesion has occurred—may involve the extremities as
well.6Varicella-zoster is primarily a disseminated skin infection in
children, but susceptible adults also may develop that condition,
especially if they are immunocompromised.7 The lesions in both
diseases are vesicobullous, grouped, and painful; they are often
preceded by a prodrome of localized dysesthesia or pruritus.
Zoster is typified by an anatomic distribution that follows the
dermatomes.6 Because Herpes family viruses are rarely if ever
cleared by the host, they persist in occult clinical form in the
sensory ganglia of the peripheral nervous system. 8 Under favor-
able clinical conditions, the viruses may again replicate actively
and cause recurrent skin lesions.
The microscopic appearances of lesions caused by H. simplex
and V. zoster are identical (Figs. 2 and 3). In classic form, they are
respresented by intraepidermal or transepidermal vesicles and
bullae, or by shallow ulcers. One sees keratinocyte ballooning,
acantholysis, and necrosis. The infected epidermal epithelial cells
are large and pale, with blue-gray nuclei, marginated chromatin,
and, potentially, intranuclear inclusions. Multinucleation and nu-
clear molding are also common. 8 Additional helpful findings in-
clude cytopathic changes in dermal appendages, as well as in-
trabullous and periappendigeal infiltrates of neutrophils, lym-
phocytes, and plasma cells. In some instances, leukocytoclastic
small-vessel vasculitis may be present as well. 9 The lymphoid cells
may be enlarged and sufficiently cytologically-atypical that a di-
agnosis of lymphoma, leukemia, or plasmacytoma can be seriously
considered.8,9 Those misinterpretations are possibly furthered by
the fact that the atypical mononuclear cells may be im-
munoreactive for CD30 or CD56, both of which can be associated
with true hematopoietic malignancies in the skin.8 However, ad-
ditional immunostains 10 or in-situ hybridization studies will re-
solve diagnostic uncertainty by showing the presence of virus-
related proteins and nucleic acids in infections with Herpesviridae.
Immunobullous dermatoses
Several bullous cutaneous diseases reflect the presence of auto-
immune processes that involve, or are directly specifically at, the skin.
These can be divided into two broad subcategories—intraepidermal
bullous disorders and subepidermal bullous conditions.

Fig. 2. Herpes simplex dermatitis is shown on the finger of a person who touched an active herpetic lesion on someone else (left). The lesion is represented by an in -
flammatory blister (top right), filled with dyshesive keratinocytes that show blue-grey nuclei, multinucleation, and margination of chromatin (bottom right).
252 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260

Fig. 3. Varicella-zoster dermatitis (shingles) usually assumes a topographic distribution that follows dermatomes (left). The histological and cytological features of the
keratinocytes in lesional blisters are essentially the same as those seen in Herpes simplex infections (right panels).

Intraepidermal immunobullous disease—pemphigus variants
As a generic condition, pemphigus is a blister-forming disorder
that is caused by circulating autoantibodies to the desmogleins
(principally types 1 and 3). 11 They are attachment proteins within
desmosomal complexes; hence, when they are damaged im-
munologically, intercellular dyshesion occurs easily. At sites of
minor friction against the body surface—in many anatomic loca-
tions— fluid-filled bullae are formed, and such lesions also are
seen in mucosal surfaces. The blisters are extremely friable and
easily broken, leaving raw skin surfaces that may become
superinfected.5,12-22
Pemphigus typically develops in adults between the ages of 40 and
60 years, and persons of Ashkenazi Jewish heritage are over-
represented. However, children may also be affected, and a pecu-
liar geographic “hot-spot” is present in Brazil, where a variant of the
disease called “fogo selvagem” is prevalent.20,21
Histologically, two main forms of pemphigus are recognized—
pemphigus vulgaris and pemphigus foliaceus. 16-19 The first
shows intraepidermal acantholysis which is centered just above
the basal layer; basal cells themselves and the upper layers of the
epidermis retain retain relatively intact intercellular cohesion
(Fig. 4). Mucosal epithelium may be similarly affected. In
pemphigus foliaceus, the acantholytic zone is instead at the level
of the granular layer (Fig. 5). Both forms of the disease can involve
the dermal appendages as well, and both may be accompanied by
a sparse perivascular and interstitial dermal infiltrate of lympho-
cytes, with neutrophils and eosinophils as well in some cases. By
DIFM or indirect immunofluorescence microscopy (IIFM)—in
which patient serum is incubated with sections of monkey eso-
phagus and then with fluorescein-labeled antihuman im-
munoglobulin—one sees peripheral labeling of epidermal kerati-
nocytes with a lacework-like pattern.23 The usual endogenous
immunoreactants in DIFM are IgG and C3; rare cases may show
labeling for IgA instead. 14,18
Other uncommon subtypes of pemphigus are represented by
pemphigus vegetans, pemphigus erythematosus, pemphigus her-
petiformis, paraneoplastic pemphigus foliaceus, and drug-induced
pemphigus foliaceus.18,24,25 They are sufficiently rare that a dis-
cussion of their attributes will not be presented here.
Subepidermal immunobullous dermatoses
The principal immunobullous dermatoses that cause blisters to
form beneath the epidermis are three in number—bullous pem-
phigoid/pemphigoid gestationis (BPPG); epidermolysis bullosa

Fig. 4. Pemphigus vulgaris presents with flaccid bullae on the trunk and on mucosal surfaces that rupture easily, leaving raw surfaces (top panels). Histologically, the lesions
demonstrate suprabasal acantholysis and are relatively non-inflammatory (bottom left). Indirect immunofluorescence studies show peripheral, cell-membrane based la-
beling for IgG (bottom right).
 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260
Fig. 5. Pemphigus foliaceus manifests as blisters that form primarily on the trunk. They rupture readily and leave eroded sur faces, or scaly-crusty lesions on an erythematous base
(left). Microscopic examination shows acantholysis in the upper layers of the epidermis, with little inflammation (right).
acquisita (EBA); and the IgA-related dermatoses. The last of those
categories includes dermatitis herpetiformis and chronic bullous
disease of childhood/linear IgA disease.
BPPG: Patients with bullous pemphigoid are typically older
than 50 yrs; the main exception to that statement concerns wo-
men with pemphigoid gestationis (formerly called herpes
gestationis).5,13,14,20,26,27 It may be clinically manifest with a non-
specific pruritic rash; eczema-like eruptions; urticarial and an-
nular lesions; or vesicles and bullae. Lesions may be disseminated
or localized to one region of the skin, and involvement of the
mucosae is usually absent. Some elderly patients may have pre-
ceding neurological diseases (e.g., stroke; Parkinson disease, etc.)
or visceral malignancies such as renal cell carcinoma and chronic
lymphocytic leukemia.13,14,28 Pemphigoid gestationis develops
during the second or third trimesters of pregnancy. 26
BPPG is caused by the spontaneous formation of IgG or IgE au-
toantibodies, or both, and activated T-lymphocytes that are directed
at proteins BP180 (BPAG2) or BP230 (a plakin). Those moieties are
located in the NC16A domain of collagen type XVII in the lamina
lucida of the epidermal basement membrane (EBM) (Fig. 6), and
they are associated with hemidesmosomes.5,13,14,20,29,30 The reason
for an association between this particular autoimmune process and
gestation is unknown.
In the prodromal stage before vesicles or bullae develop, skin
biopsies of BPPG show a histological image like that of urticarial
dermatitis with numerous intradermal eosinophils.31 Only later in
the clinical evolution do subepidermal blisters become apparent
microscopically. These contain serum and a mixture of eosinophils
with a lesser number of neutrophils and lymphocytes (Fig. 7). As
the lesions progress, reepithelialization of the blister bases may
Fig. 6. This cartoon of the epidermal basement membrane zone shows the relative
locations of antigens that are targeted in the immunobullous dermatoses.
253
occur, potentially causing confusion as to whether the defect is
subepidermal or intraepidermal.
DIFM demonstrates linear labeling for IgG or C3, or both, at the
EBM in these disorders. 20,23,30,32 A convenient way to show that
the split in the basement membrane is high in the lamina lucida is
the use of immunostains for collagen type IV (CIV) in paraffin
sections of lesional skin.33 Reactivity for CIV will be seen in the
base of the blisters.
EBA: EBA is an immunobullous dermatosis and can also be a
mechanicobullous disorder. The latter of those terms refers to the
tendency for bullae to form in skin areas that easily undergo minor
injury, such as the hands and feet. Other examples of the disease
can be generalized in lesional distribution, and the mucosal sur-
faces may be involved as well. EBA affects adults, usually in middle
age. The bullae heal with scarring, often with formation of sec-
ondary milia.34,35-40
Autoantibodies in EBA are directed against the NC1 domain of
type VII collagen, in the lamina densa of the EBM. 5,20,30,34,35 DIFM
studies show a pattern of immunoreactivity for IgG or C3, or both,
which is superimposable on that seen in BPPG cases. 32,36 However,
the two disorders can be separated from one another by the afore-
mentioned staining method for CIV in paraffin sections. In contrast
to BPPG, reactivity for CIV is present in the roof of the
blisters.33(Fig. 8).
Dermatitis herpetiformis (DH): Although the name of this
condition might suggest an infectious etiology, the term “herpeti-
formis” is meant only to suggest a clinical similarity to the lesions of
Herpes simplex. As stated above, the etiology of DH is host
autoimmunity.5,20,41 In contrast to other immunobullous disorders,
however, the trigger for this process is known in DH patients. They
are usually young or middle-aged adults, who show an over-
representation of human leukocyte antigens DQ2 and DQ8. Most
patients (90%) have concomitant celiac disease (sprue), and some
have other autoimmune diseases as well, including Hashimoto
thyroiditis, pernicious anaemia, juvenile diabetes mellitus, vitiligo,
and Addison disease. Circulating IgA antibodies are detectable that
may be directed at endomysial proteins, tissue transglutaminase,
epidermal transglutaminase, and deamidated gliadin peptide.42-45
DH and sprue are caused by an allergy to the gliadin fraction of
gluten proteins, which are present in foods containing wheat, rye, and
barley.45 IgA antibodies are formed against that substance and they
also react with the skin and the small intestinal mucosa.
Celiac disease is associated with DH in 15-25% of patients who
present with the first of those conditions, causing malabsorption
with weight loss and abdominal discomfort.42-45
254 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260

Fig. 7. Bullous pemphigoid may present with a nonspecific erythematous, urticarial, or eczema-like eruption, or with blisters that can be localized or widespread on the trunk
and extremities (top left). It manifests microscopically as subepidermal bullae that are filled with eosinophils, and a lesser number of neutrophils and lymphocytes (top right and
bottom left). Note that the lesion shown in the top right panel has begun to reepithelialize at its base. Direct immunofluorescence studies demonstrate linear labeling of the
epidermal basement membrane zone for IgG (bottom right).

The lesions of DH typically affect the scalp, trunk, knees, and
elbows. They are intensely pruritic and vesicular or bullous, and
may be grouped or arranged in a serpiginous configuration. Strict
elimination of gluten from the diet commonly results in the re-
mission of both DH and sprue. 45
Histologically, DH shows the presence of subepidermal blisters
that begin over the dermal papillae and then become confluent.
They are filled predominantly by neutrophils, with a minor po-
pulation of eosinophils.44(Fig. 9). DIFM demonstrates granular
deposits of IgA in the EBM, mainly distributed over the papillary
tips. IIFM can be employed to show the presence of anti-en-
domysial IgA antibodies in serum.23,32
Linear IgA disease/chronic bullous disease of childhood: These
rare conditions differ from DH because no food allergies are as-
sociated with them. Children with chronic bullous disease are
usually prepubertal, and they develop bullous lesions that begin in
the genital skin before involving the trunk, face, and extremities.
Spontaneous linear IgA disease is seen in middle-aged adults,
presenting with blisters and bullae on the limbs or trunk; the
mucosae are also involved in roughly one-half of cases. 46,47 A
proportion of those patients have inflammatory bowel disease,
and some have hematolymphoid malignancies, rheumatologic
conditions, or malignant solid tumors. 48,49 Certain medications
also may trigger the development of linear IgA disease—notably, the
antibiotic vancomycin.46,50
The lesions are often annular or targetoid, and new blisters may
erupt around older ones or in clusters. Ulcers and scars eventuate as
the disease evolves.
Microscopically, linear IgA disease is essentially identical to DH,
except that broader areas beneath the epidermis are filled by
confluent infiltrates of neutrophils (Fig. 10). The name “linear” IgA
disease derives from the DIFM pattern in that condition. IgA is
deposited at the EBM in a linear continuous fashion, sometimes
with C3 as well.46,49,51
Non-infections & non-immune bullous dermatoses
As expected, non-infectious, non-immune bullous disorders
can be identified definitively only after DIFM or IIFM studies have
been performed and infections have been excluded. By definition,
no immunoreactants are present in tissue samples from those
conditions, which include hereditary epidermolysis bullosa (HEB)

Fig. 8. Epidermolysis bullosa acquisita (EBA) manifests with bullae that are principally located on the extremities (top left ). The microscopic image of the lesions mimics that
of bullous pemphigoid (top right), as do the results of direct immunofluorescence studies for IgG (bottom left). EBA can be separated from pemphigoid by performing
immunostains for collagen type IV (CIV) on paraffin sections of the lesions; CIV is seen in the roof of the blisters in EBA (bottom right), but it is located in their ba ses in
pemphigoid.
 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260 255

Fig. 9. Dermatitis herpetiformis (DH) causes intensely-pruritic blisters to form on dorsal skin surfaces, and these may rupture (top left). The microscopic image of DH
features subepidermal collections of neutrophils, which are concentrated in the dermal p apillae (top right & bottom left). Direct immunofluorescence studies show dis-
continuous deposits of IgA in the epidermal basement membrane (bottom right).

Fig. 10. Linear IgA disease presents with large flaccid bullae that rupture (left). The histologic picture of this disease is like that of dermatitis herpetiformis, but subepi dermal
neutrophilic infiltrates tend to be more confluent (right).

variants; Hailey-Hailey disease (HHD); porphyria cutanea tarda The histologic findings in all epidermolysis bullosa variants
(PCT); and bullous drug eruptions or bullous arthropod bite feature the presence of a “clean,” non-inflammatory bulla beneath
reactions. the epidermis (Fig. 11). The various genetic subtypes must be
identified and separated from one another by genetic testing for
52-54
Inherited epidermolysis bullosa known mutations.

Congenital epidermolysis bullosa is a mechanicobullous con- Porphyria cutanea tarda

dition that may be inherited with either an autosomal-dominant
or an autosomal-recessive Mendelian pattern.52-54 Several clinical
variants exist, and they are related to gene mutations that relate to
synthesis of specific keratin subtypes or integrins. 53,55 They in-
clude epidermolysis bullosa simplex (EBS); junctional epidermo-
lysis bullosa (JEB); dystrophic epidermolysis bullosa (DEB); and
cases with mixed patterns. 56,57 EBS is the form that most often
yields skin biopsy specimens, because a common variant of it has
the mildest clinical manifestations. 58 Those include blisters and
bullae at sites of minor cutaneous damage, such as the hands and
feet, and such lesions begin to appear in childhood. Patients with
clinically-severe EBS, JEB, and DEB have bullous lesions at birth or
shortly afterwards, and the internal mucosal surfaces of the eso-
phagus and anorectal area also may be affected. JEB is often mu-
tilating and it compromises life expectancy. 57
PCT is the most common form of porphyria. It is caused by
defective function of uroporphyrinogen decarboxylase, which is
instrumental in the formation of hemoglobin. Approximately 20%
of patients have the disease as an autosomal-dominant genetic
condition, whereas the remaining cases are sporadic. 59 Pre-
cipitating or contributing comorbid conditions include alcoholism;
hepatitis-C; hemochromatosis; the use of exogenous estrogen-
containing medications; and environmental exposure to certain
polycyclic hydrocarbons.60-62
Clinically, patients with PCT have increasingly fragile skin on
the dorsal hands and the forearms, and they are photosensitive.
Erosions develop after relatively minor injuries; vesicles, bullae,
and milia are also seen. Hyperpigmentation and hirsutism are
common in the skin of the face and neck, and morphea-like
256 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260

Fig. 11. Inherited epidermolysis bullosa simplex is shown here, represented by bullous lesions that form at sites of minor tr auma (left panels). Microscopically, a non-
inflammatory subepidermal bullae is evident (right).

changes also may occur there. The urine is usually reddish or tea-
colored—at least intermittently—and it contains an excess of
uroporphyrinogen.59
Histologically PCT manifests as acellular, non-inflammatory
subepidermal bullae. It features a singular “festooning” pattern of
the vascular cores of dermal papillae in the floor of lesional blis-
ters, owing to reduplication and thickening of vascular basement
membranes.59,62(Fig. 12). These can be accentuated with the di-
gested periodic acid-Schiff (PAS-D) method. Moreover, many ex-
amples of porphyria demonstrate the presence of so-called “ca-
terpillar bodies” (pink serpiginous structures) in the blister cavity,
near its roof. Such inclusions are conjointly formed by fragments
of epidermal cytoid bodies, collagen, and EBM. These inclusions
are also reactive with the PAS-D stain, and are felt to be virtually
diagnostic of PCT.63
Hailey-Hailey disease (“Benign familial pemphigus”)
Hailey-Hailey disease (HHD) is a genodermatosis that causes
sterile, non-inflammatory, acantholytic bullae to form, most often
in intertriginous skin areas.64,65 It typically becomes apparent
during the third or fourth decade of life, as a painful and erosive
erythematous rash in the axillae, groin, neck, inframammary skin,
or gluteal cleft. Painful maceration may occur, along with
secondary superinfection. Either bacteria or Herpes simplex may be the
responsible infectious organisms. As the lesions evolve their central
areas become normalized, leaving an annular profile. Hot weather
and friction worsen the severity of the disease.65
HHD is an autosomal-dominant disease with incomplete pe-
netrance. Its underlying genetic aberration The cause of the dis-
ease is a defect in the ATP2C1 gene on chromosome 3; it encodes the
hSPCA1 polypeptide, which influences intracellular calcium flux.64
Local calcium levels are crucial to the assembly of desmo-
somes in the surface epithelium.66-69
Microscopically, HHD is a panepidermal, non-inflammatory,
acantholytic process. The resulting image is said to resemble a
“dilapidated brick wall” (Fig. 13). Erosion of the lesions is
common.64
Bullous drug eruptions
As stated above, selected drugs may induce a bullous auto-
immune process with cutaneous manifestations. Prime examples
are the associations of secondary bullous pemphigoid or pem-
phigus with the use of penicillamine, angiotensin converting en-
zyme-inhibitors, gold salt injections, beta-lactam antibiotics, ri-
fampicin, nifedipine, propranolol, and phenobarbital, or the ad-
ministration of vancomycin with subsequent linear IgA

Fig. 12. Porphyria cutanea tarda (PCT) causes blisters to form in sun-exposed skin areas (left). They are non-inflammatory, and blood vessels in the bases of the bullae have
reduplicated basement membranes, causing a “festooning” pattern (right).
 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260
Fig. 13. Hailey-Hailey disease (HHD) is an inherited dermatosis caused by mutations in a gene that influences intracellular calcium flux. It manifests as easily-eroded bullae in
intertriginous skin areas (left). Histologically, these demonstrate non-inflammatory acantholysis throughout the epidermal thickness (right panels).
dermatosis.46,50,70 However, in other instances, a bullous drug
eruption is non-immune in nature and subepidermal in location.
As Weyers & Metze have indicated,71 the majority of such reactions
begin as an interface dermatitis that progresses to blister formation.
Necrotic keratinocytes and basal epidermal vacuolar changes at the
margins of a bulla are highly suggestive of that mechanism. Some
bullous drug eruptions are paucicellular or non-inflammatory, whereas
others may feature intrabullous neutrophils or eosinophils.71
Bullous arthropod bite reactions
Several arthropod assault reactions may feature the formation
of non-immune bullous lesions, which may be subepidermal or
both intraepidermal and subepidermal in location. Responsible
biting creatures include bedbugs, midges, mites, flies, and
mosquitoes.72-74 The clinical history and physical examination are
obviously key points in the recognition of such lesions. Micro-
scopically, one sees a significant eosinophilic infiltrate in the der-
mis—particularly around appendages 72—and within the bullae
themselves, and small-vessel vasculitis may be present as well. 74
“Pseudobullous” dermatoses
Some disorders have histological attributes which suggest that
they may cause clinical vesicles and bullae, but empirical ob-
servation shows that they do not. As such, these conditions may be
classified as “pseudobullous.”
Darier disease
Darier disease (DD) is another inherited (autosomal-dominant)
disorder affecting epidermal keratinization. The underlying defect
is mutation of the ATP2A2 gene, which encodes ATPase-2 (SER-
CA2), an endoplasmic reticulum-based calcium pump.68,69,75 This
condition typically develops in childhood and becomes manifest
with small, rough, skin-colored or brown papules that favor the
face, chest, and back. The eruption may be associated with a dis-
agreeable odor; secondary scales and crusts may develop as well 76.
Histologically, DD is characterized by suprabasal acantholysis,
with the formation of eosinophilic dyskeratotic cells (“corps ronds”
[French for “round bodies” or “orbs]) and grains (eosinophilic an-
ucleate keratinocytes).76(Fig. 14). Zones of intraepidermal cellular
dyshesion often have a wedge-shaped configuration.
257
Grover disease (Transient acantholytic dermatosis)
Grover disease (GD) is an acquired, acantholytic, and dysker-
atotic condition that overwhelmingly affects men in middle age
and beyond. The truncal skin is favored, where one sees groups of
red-brown, crusted, or eroded papules that are often intensely
pruritic. This condition has no known cause and is self-limited.77
At a microscopic level, the lesions of GD are either indis-
tinguishable from those of DD, or they resemble the image of
pemphigus vulgaris “in miniature”.78(Fig. 15). Clinical data permit a
confident distinction between those disorders to be made.
Pustular dermatoses
In addition to cutaneous infections (with various bacteria,
viruses, and fungi) and drug eruptions, several other cutaneous
disorders can be characterized by the formation of intraepidermal or
dermal pustules. These include pustular psoriasis, subcorneal
pustulosis (Sneddon-Wilkinson disease), and acute generalized
exanthematous pustulosis.
Pustular psoriasis
Pustular psoriasis may be localized, or it may become manifest
with small, sterile, pustular lesions—which are sometimes con-
fluent—in several skin areas. Patients with disseminated disease
are usually febrile and systemically ill. Indeed, some require ad-
mission to burn units and have life-threatening illness. 79,80
Disseminated pustular psoriasis may appear for the first time
during pregnancy, and “chronic palmoplantar pustulosis” is also
regarded by many observers as a variant of psoriasis. Both children
and adults can be affected. 81
This disorder demonstrates the formation of intraepidermal
pustules, which may be subcorneal, and interstitial neutrophilic
infiltrates in the papillary dermis. Variable psoriasiform acanthosis
and epidermal hyperplasia are also seen. 79
Subcorneal pustulosis
Subcorneal pustular dermatosis presents with multiple soft
pustules on the trunk, especially in intertriginous areas. The le-
sions resolve after several days, yielding scaly areas, and then they
are replaced by new crops of pustules.81-83 Pruritus is sometimes
present, but there are no systemic symptoms or signs. The disease
258 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260

Fig. 14. Darier disease is another genetic calcium-flux disorder. Rather than producing bullae, it presents with reddish-brown crusted papules on the trunk, face, and
extremities, which may become confluent (left). Suprabasal and mid-epidermal acantholysis is apparent microscopically, with formation of densely-eosinophilic nucleated
keratinocytes (corp ronds) and anucleate eosinophilic cells (grains) (right panels).

Fig. 15. Grover disease is an acquired disorder that primarily affects middle-aged and elderly men. It manifests with crops of pruritic, brown-red papules in the skin of the trunk
(left). These have histological appearances that may imitate those of Darier disease (top right) or pemphigus vulgaris “in miniature” (bottom right).

Fig. 16. Subcorneal pustulosis (Sneddon-Wilkinson disease) causes soft, broadly-based pustules to form in the skin of the trunk, favoring intertriginous skin areas (left). One sees
subcorneal accumlations of neutrophils microscopically (right).
 M.R. Wick / Seminars in Diagnostic Pathology 34 (2017) 250-260
may last for several years, and may occur at any age. However,
most patients are middle-aged or elderly. 83 Whether or not
Sneddon-Wilkinson disease is actually related to pustular psoriasis is
still controversial.81 An association may exist in some patients with
an underlying plasma cell dyscrasia, 84 and some individuals also
have pyoderma gangrenosum. 81
As the name of the disorder suggests, it is characterized by
collections of neutrophils beneath the stratum corneum (Fig. 16).
The dermis is relatively normal. 82
Acute generalized exanthematous pustulosis
Acute generalized exanthematous pustulosis (AGEP) is almost
always a special form of drug eruption. 85-88 It presents with nu-
merous pustules on an erythematous base on the face or the groin
and axillae, and then becomes disseminated. Patients of all ages
may be affected. Medications that are associated with AGEP in-
clude the β-lactam antibiotics, tetracyclines, sulfonamides, oral
antifungal agents, calcium channel blockers, and carbamazepine,
among others. 87 The skin eruption typically begins within 1-2
days of beginning a new medication. Uncommonly, infections by
Epstein-Barr virus, enterovirus, adenovirus, cytomegalovirus, he-
patitis B virus, and other microbes can be triggers for AGEP in
children.89 This condition may be associated with mutations of the
IL36RN gene, predisposing patients to pustule formation when
given selected medications. Similar mutations have been detected
in individuals with generalized pustular psoriasis and palmo-
plantar pustulosis.
The microscopic appearance of AGEP is essentially identical to
that of pustular psoriasis and Sneddon-Wilkinson disease. Hence,
one sees dense aggregates of neutrophils under the stratum cor-
neum with an unremarkable corium.81
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