A histopathologic study of arthropod bite reactions in 20 patients highlights relevant adnexal
involvement
Maria Miteva 1 , Peter Elsner 1 Mirjana Ziemer 1
1
Department of Dermatology, Friedrich-Schiller-University, Jena, Germany
Correspondence to Mirjana Ziemer, MD, Department of Dermatology and Allergology,
Friedrich-Schiller-University. Erfurter Strasse 35, 07743 Jena, Germany
Tel: +493641937441
Fax: +493641937423
e-mail: mirjana.ziemer@derma.uni-jena.de
Copyright © 2008 John Wiley & Sons A/S
Miteva M, Elsner P, Ziemer M. A histopathologic study of arthropod bite reactions in 20
patients highlights relevant adnexal involvement.
J Cutan Pathol 2009; 36: 26–33. © 2008 John Wiley & Sons A/S.
ABSTRACT
Background: Insect bites produce diverse skin reactions. Although quite common, the
histopathologic features of arthropod assaults have not ever been studied systemically.
Materials and methods: Twenty biopsies from cases, clinically diagnosed as arthropod bite
reactions between January 2003 and June 2007 were reviewed retrospectively. The aim of the
study was to verify as to whether reliable histopathologic criteria could be established based on
the frequency of findings observed.
Results: Epidermal spongiosis (present in 16 of 20 cases), in particular spongiosis of the
infundibular epithelium and acrosyringia as well as eosinophilic spongiosis, emerge as relevant
diagnostic clues. A moderately dense, superficial and deep infiltrate consisting mainly of
lymphocytes and eosinophils was prevalent in the dermis, with eosinophils tending to
interstitial and periadnexal distribution. Of note, 19 of 20 (95%) cases revealed periadnexal
involvement, whereas 16 of 20 (80%) had the infiltrate extending particularly along the sweat
ducts and the coiled glands. In three biopsies, concomitant involvement of sweat glands, hair
follicles and sebaceous glands was noted.
Conclusion: A practical histopathologic algorithm of arthropod bite recognition is proposed.
The involvement of the sweat glands in the pattern of arthropod bite reaction is suggested as a
new reliable diagnostic clue.
Accepted for publication January 2, 2008
DIGITAL OBJECT IDENTIFIER (DOI)
10.1111/j.1600-0560.2008.00992.x About DOI
Article Text
Insect bites and stings to humans are relative common events. Four principal arthropod classes
can be differentiated, i.e. Crustacea (shrimps, prawns, crabs and lobsters), Myriapoda
(centipedes, millipedes), Arachnida (spiders, ticks, scorpions) and Insecta (flies, mosquitoes,
midges, beetles, fleas, bugs, wasps, bees, ants, cockroaches, etc.).1,2 However, apart from ticks,
assaults by insects in particular by mosquitoes, fleas, and bugs as well as wasps, and bees are
most commonly encountered within our latitudes. However, bee and wasp stings are rarely
biopsied as they hardly ever raise diagnostic difficulties.
Various cutaneous lesions (maculae, urticae, papules, vesicles, pustules, bullae, nodules,
erosions and excoriations) could be observed in response to insect bites.3,4 As these reactions
are not highly specific for a particular arthropod and vary from one person to another,5 the
distinction from other cutaneous diseases might be difficult based on clinical grounds alone.
Hence, a histologic examination may be of diagnostic help.
However, the histopathology of insect bites may also vary significantly as it depends on many
factors, such as the nature of the arthropod, the duration of the lesion, the immunological
reaction, the presence of arthropod parts and the discharge of toxins.3,6 Therefore, a unifying
concept of the most relevant histomorphologic phenomena is hardly realistic. The
histopathologic features of arthropod reactions are insufficiently documented and have not been
studied systemically. Descriptions in textbooks are brief, further not congruent3,4,6–8 (Table 1).
Table 1. Histopathologic findings in arthopod bite reactions retrieved from textbooks
References
Histopathologic findings
Ackerman et Early
al. 3,7
Wedge-shaped perivascular (lymphocytes and eosinophils) and interstitial
infiltrate (of scattered eosinophils), a few neutrophils may be discernible
Slight edema of the papillary dermis
(A discrete) focus of spongiosis at the very site of the bite, directly above the
apex of the wedge infiltrate
Spongiotic infundibulitis in the center of the wedge-shaped infiltrate
Fully developed
Denser and deep inflammatory infiltrate; the subcutaneous fat may be
affected
More marked edema and spongiosis (multiloculated vesicles, becoming
smaller the farther they are)
Late
8
Elder et al.
Erosion, ulceration or crust likely to occur, secondary to scratching
Mosquitoes
Many neutrophils during the early toxic response and a mononuclear infiltrate
of lymphoid cells and plasma cells during the later response; lack of
eosinophils or few of them present
In papular urticaria
Edema and spongiosis in stratum malpighii
Kerl et al.4
Inflammatory infiltrate around the vessels of the dermis, extending into the
lower dermis (containing eosinophils)
Superficial and deep, perivascular and interstitial infiltrate (lymphocytes and
eosinophils)
Wedge-shaped form of the infiltrate
Focal spongiosis (with vesicles, becoming smaller the farther they are)
The spongiosis is mostly pronounced directly above the apex of the wedge
infiltrate
Weedon et
al.6
Edema in the papillary dermis
In papular urticaria
Edema in the papillary dermis
Superficial and deep infiltrate with perivascular accentuation and usually
some interstitial eosinophils
Neutrophils in the early biopsies lesion (especially in flea bites)
In persistent insect bites – plasma cells may be prominent, particularly in the
deep dermis; pseudoepitheliomatous hyperplasia; atypical dermal infiltrates
Focal epidermal necrosis is possible
Besides, there is a lack of evidence-based data in the literature, dealing with the particular
nature of the infiltrate in arthropod bites. To our knowledge, there is only one study aimed at
the evaluation of morphologic and immunohistochemical properties of the lesions in papular
urticaria (a kind of reaction to certain bites).9 However, the immediate aim of that study was
rather to analyze the phenotype of the infiltrate and the role of the type I hypersensitivity
reaction in the pathogenesis of papular urticaria, than to evaluate the main characteristics of its
histopathologic pattern.
This is the first study aimed at investigating the particular histomorphological features in
arthropod bite lesions. Several previous studies have been focused on the histologic hallmarks
in biopsies of patients who experienced assaults by particular arthropods, such as fleas,10 ticks
and mites,11–16 sea urchins17 and spiders.18 Others have studied the predominant morphologic
changes caused by insect bites, yet only in particular populations such as patients with
concomitant neoplasms,19–21 positive for the human immunodeficiency virus 22 or with various
other diseases.23
Series of biopsies obtained from patients with a clinical presentation of arthropod assaults
(mosquitoes, fleas, bugs and ticks) who passed through our department recently, histologically
revealed a mixed infiltrate with special predilection to the adnexal structures. On this empirical
basis, we assumed that the involvement of the adnexa is a rather 'natural phenomenon' than a
casual finding in cutaneous reactions to arthropod bites, a fact previously vaguely reported.
We reinvestigated 20 biopsy specimens diagnosed clinically and pathologically as insect bite
reactions. The aim of the study was to verify and update the morphologic criteria established as
well as to specify new helpful clues.
Materials and methods
Twenty-one biopsy specimens obtained from 21 patients diagnosed clinically and histologically
with arthropod bite reactions between January 2003 and June 2007 were studied. One biopsy
was discarded because only superficial epidermal substrate was present, thus realizing a total of
20 biopsies. Clinical data were retrieved from the file register of the Department of
Dermatology (Friedrich-Schiller-University, Jena, Germany). Special attention was paid to
patient's age, sex, complete medical history, clinical symptoms and morphology of the lesions.
The biopsy specimens comprised 4- to 6-mm punch biopsies (n = 14) and excisional biopsies (n
= 6). They had been fixed in 4% buffered formalin and processed further according to the
routine methods. A mean number of 3 sections stained with hematoxylin and eosin were
examined in all cases.
To assess the specificity of criteria for histopathologic diagnosis of arthropod reactions and to
achieve compelling results, only cases with a documented clinical presentation of an arthropod
assault (Figs. 1a and 2a) were included. Furthermore, we employed a provisional set of criteria
to allow for the thorough evaluation of the samples including the already established
morphologic criteria for insect bite reactions (Table 1). All slides were studied for the presence
of the following features.
Fig. 1. 1A) Urticarial papules on erythematous ground are
distributed in a random pattern on the trunk. This clinical
manifestation is consistent with an arthropod-bite reaction.
1B and 1C (from patient on figure 1A). A moderately
dense, superficial and deep, perivascular, periadnexal and
interstitial infiltrate composed of lymphocytes and
eosinophils (hematoxylin and eosin; 1B, original
magnification ×40; 1C, original magnification ×200).
[Normal View ]
Fig. 2. 2A) Urticarial papules on erythematous ground are
distributed in a random pattern on the trunk. This clinical
manifestation is consistent with an arthropod-bite reaction.
2B, 2C (from patient on figure 2A). A moderately dense,
superficial and deep, perivascular, periadnexal and
interstitial infiltrate composed of lymphocytes and
eosinophils (hematoxylin and eosin; 2B, original
magnification ×40; 2C, original magnification ×200).
[Normal View ]

1.
Epidermal changes: presence of crust, erosion/ulceration, ortho/hyperkeratosis,
parakeratosis, acanthosis, lichen simplex chronicus-like-features (concomitant presence
of acanthosis, hypergranulosis and hyperorthokeratosis) and spongiosis.

2.
Spongiosis of follicular infundibula and acrosyringia.

3.
Edema in the papillary dermis.

4.
Cell composition, density, depth and distribution of the inflammatory infiltrate.

5.
Wedge-shaped form of the infiltrate, defined as V-shaped arrangement of the
inflammatory cells in the dermis with the apex toward the subcutaneous fat and a focus
of spongiosis/erosion/crust situated directly above the apex of the wedge.

6.
Flame figures (clusters of eosinophils around bundles of degenerated collagen).

7.
Extravasations of erythrocytes.

8.
Signs of vasculitis.
Statistical analysis was carried out on a descriptive and analytical basis.
Results
The sample consisted of biopsies obtained from 12 men and 8 women, with a mean age of
51 years (range 4–89 years).
The histopathologic features observed are summarized in detail in Table 2.
Table 2. Evaluated histopathologic features
Histopathologic features
Epidermal changes
Number of biopsies (%)
Spongiosis
18 (90)
Within the epidermis
16 (80)
Spongiotic infundibulitis/spongiotic acrosyringitis 15 (75)
Epidermal and adnexal
5 (25)
Accompanied by vesicles/vesiculopustules
4 (20)
Eosinophilic spongiosis
3 (15)
Erosion/ulceration
5 (25)
Scale-crust with neutrophils
7 (35)
Mild acanthosis
7 (35)
Ortho/hyperkeratosis
9 (40)
Focal parakeratosis
6 (30)
LS-like features
7 (35)
Dermal changes
Subepidermal edema
7 (35)
Inflammatory infiltrate
20 (100)
Components of the infiltrate
Lymphocytes
20 (100)
Eosinophils
20 (100)
Neutrophils
11 (55)
Macrophages
11 (55)
Plasma cells
0 (0)
Depth of the infiltrate
Superficial and deep
19 (90)
Superficial
1 (5)
Density of the infiltrate
Moderately dense
17 (75)
Dense
1 (10)
Sparse
2 (10)
Distribution of the infiltrate
Perivascular, periadnexal and interstitial
16 (80)
Perivascular and periadnexal
4 (20)
Perivascular and interstitial
0 (0)
Involvement of the adnexal structures
19 (95)
Sweat glands
16 (80)
Hair follicles
8 (40)
Sebaceous glands
6 (30)
Wedge-shaped form of the infiltrate
7 (35)
Other features
Extravasations of erythrocytes
Flame figures
Swollen vessel walls and/or dilated vessels
Eosinophilic panniculitis
4 (20)
3 (15)
2 (10)
1 (5)
Epidermal changes were determined in most biopsies (n = 18, 90%). Spongiosis was the most
relevant finding as it was apparent in 18 biopsies (90%). Within the epidermis, it was
determined in 15 cases (75%), whereas spongiotic infundibulitis and/or spongiotic
acrosyringitis (spongiosis in the acrosyringeal portion of the eccrine duct) were available in
five biopsies (25%). Epidermal as well as adnexal spongiosis was present in four biopsies
(20%). Exocytosis of eosinophils into the epidermis with particular accumulation within
intraepidermal vesicles – a phenomenon referred to as eosinophilic spongiosis – was displayed
in five biopsies (25%) (Fig. 3).
Fig. 3. Focal accumulation of neutrophils and in particular
eosinophils within a spongiotic epidermis. (hematoxylin
and eosin, original magnification ×200).
[Normal View ]
Most biopsies were characterized by a moderately dense (n = 17, 75%), superficial and deep
inflammatory infiltrate (n = 19, 90%). In the majority of the biopsies (16 biopsies, 80%) it was
distributed in a perivascular, periadnexal and interstitial pattern (Figs. 1b, 2b and 4a). Features
of periadnexal involvement (either of the sweat glands, hair follicles or sebaceous glands) were
displayed in 19 of 20 biopsies (90%). The sweat glands seemed to be completely implicated in
the inflammatory process because infiltration was observed in the acrosyringeal portion, around
and within sweat ducts as well as in the deep dermis/subcutis affecting the coiled gland
(Fig. 1c, 2c and 4a–c). Through analyzing consecutive biopsy sections, in 16 of all slides (80%)
sweat gland involvement extending along the entire structure of the glands was noted. In eight
cases (40%), the infiltrate involved the hair follicles (perifollicular/folliculocentric infiltrate)
and in six (30%), the sebaceous glands. Lymphocytes and eosinophils were the fundamental
components of the infiltrate as both were present in all biopsies examined (n = 20, 100%); in
five (25%) of them eosinophils predominated. The latter could be noted within the epidermis as
well as in the reticular dermis, scattered interstitially among the collagen fibers and accounting
occasionally for the development of flame figures (n = 3, 15%), and/or descending toward the
deeper parts of the dermis. Neutrophils were additionally present in 11 specimens (55%), being
the predominant cell component in two of them (10%). The infiltrate was estimated as wedge
shaped (V-shaped, with the base of the V in the direction of the subcutaneous fat) in seven
cases (35%). However, the small size of biopsy material did not allow for the assessment of
this peculiar form in most cases.
Fig. 4. A, B, C) Involvement of the sweat glands – from
the acrosyringeal portion, along the sweat ducts downwards
to coiled glands in the deep dermis. Note also the interstitial
distribution of the eosinophils in (B) (hematoxylin and
eosin, original magnification ×40, ×100, ×200 accordingly).
[Normal View ]
Extravasated erythrocytes (four biopsies, 20%) and swollen vessel walls and/or dilated
capillaries (n = 2, 10%) were recognized as consistent with the arthropod bite pattern because
they represent a further sign of external insult to the skin. Although nuclear dust and
extravasated erythrocytes occurred, microthrombi and fibrinoid necrosis of the vessel walls
were absent and leukocytoclastic vasculitis was not a feature (0 biopsies, 0%).
The subcutis was particularly involved in one case (10%), showing a mixed infiltrate of
lymphocytes, macrophages and numerous eosinophils, extending both within septa and lobules,
a pattern referred to as 'eosinophilic panniculitis' (Fig. 5).
Fig. 5. A mixed infiltrate of lymphocytes and numerous
eosinophils, extending into the subcutaneous fat
(eosinophilic panniculitis) (hematoxylin and eosin, original
magnification ×200).
[Normal View ]
Discussion
The histopathologic findings presented here emphasize and enhance the spectrum of knowledge
about arthropod reactions.
Spongiosis was the predominant feature characterizing the epidermal changes. Keeping in
agreement with previous data (Table 1), we observed two patterns of spongiosis – an early
discrete focus of spongiosis present in the epidermis at the very site of the insect bite and a
more extending pattern accompanied by the formation of multiloculated
vesicles/vesiculopustules.
An interesting observation was the relatively high number of biopsies disclosing spongiotic
infundibulitis and/or spongiotic acrosyringitis (25%). An ostium of an infundibulum is sampled
frequently by the insects as a site for biting because it harbors delicacies loved by them
(bacteria, yeasts, mites and lipids from the sebaceous glands).3,7 Moreover, because of the
effects of the microorganisms 'residing' in the follicle, an odor is emitted that seems to attract
the arthropods. Hence, spongiosis is formed within the infundibulum, thus specifying insect
bites as foliculocentric.7,9 The involvement of the acrosyringium in arthropod bites has been
reported in one study only,9 yet providing no evidence about the pathogenesis of this
phenomenon.
Exocytosis of eosinophils in the spongiotic foci (eosinophilic spongiosis) was presented in 25%
of all cases revealing spongiosis,3,6,7,24 and therefore, if present, should be considered as a
sensitive clue to the diagnosis. However, eosinophilic spongiosis could be observed in
heterogeneous group of dermatoses,6 the bullous diseases being among the most common to
differentiate from. Of help is the fact that in arthropod reactions, the eosinophilic spongiosis
occurs only focally and the eosinophils predominate usually in the deeper parts of the biopsy,
whereas in urticarial stages of bullous dermatoses, an extended distribution of eosinophils in
particular along the epidermal-dermal junction is expected.4
Other epidermal changes, such as the presence of a crust, erosion/ulceration, mild acanthosis,
ortho/hyperkeratosis, parakeratosis and features of lichen simplex chronicus were determined
in less of the half of our biopsy specimens. They usually occur as a secondary phenomenon in
the course of the bite reaction because of energetic scratching on the site of the assault. They,
therefore, should be applied as a diagnostic criterion with the reservation that a relatively old
lesion has been biopsied. A helpful clue might be the presence of eosinophils within the serum
crust.
Of note, eosinophils attribute a constant feature to the inflammatory infiltrate in insect bite
reactions as they were present in all cases regardless of their amount. Apart from forming
collections in spongiotic vesicles, they determine the appearance of other three phenomena –
their interstitial distribution, the formation of flame figures and eosinophilic panniculitis. Flame
figures are considered commonly a helpful clue to the diagnosis of an insect bite reaction.3,6
We identified them only in four of our biopsies. Degeneration of the dermal collagen may
result from the degranulation of the lysosomal enzymes in the eosinophils as well as from those
released by the neutrophils.3 Hence, flame figures are of minor help to the diagnosis. Moreover,
because in 50% of the cases macrophages are available, there might be a shortage of time for
the granules to act upon the collagen as the macrophages ingest the degranulated eosinophils
greedily. Besides, flame figures are considered a peculiar response to multiple factors and
therefore do not label a specific etiology.3,6,25
'Eosinophilic panniculitis' can be found as a histopathologic pattern in erythema nodosum,
vasculitis, parasitic infection, drug injections, Wells' syndrome, leukemia and in arthropod
bites.6 As the coiled glands, embedded in the subcutis, seem to be implicated considerably in
arthropod bite reactions, panniculitis may ensue. However, the presence of eosinophilic
panniculitis should be considered a helpful clue to the diagnosis only in cases of a clinical
history for arthropod bites and/or in the presence of the other relevant criteria.
In accordance to previous data (Table 1), a moderately dense superficial and deep inflammatory
infiltrate was observed in most of the biopsies revised. Most authors proclaim a perivascular
and interstitial pattern of the infiltrate's distribution.3,6–8 However, the most prevalent type of
infiltrate observed in our sample revealed perivascular, periadnexal and interstitial distribution
(80%). The periadnexal distribution of the infiltrate as a feature of an insect bite reaction has
been already alluded by Ackerman et al.3,7 who suggested that some insects (mosquitoes) seem
to bite at the site of an ostium of a hair follicle thus inducing a folliculocentric infiltrate.9
However, the probable involvement of the sweat glands has been mentioned only twice in the
available literature. Jordaan and Scheider recognized spongiotic acrosyringitis as the only
pattern of sweat gland affection,9 whereas Schaffer et al.26 remarked on the perivascular and
periappendiceal disposal of the infiltrate in the middle and lower thirds of the corium,
concentrated chiefly about the sweat glands. About 80% of the slides in our sample disclosed
sweat gland involvement extending along the entire structure of the glands as not only the
acrosyringial portion, but also the sweat ducts and the coiled glands were implicated in the
inflammation. It might be assumed that the orifice of a sweat gland is another attractive site for
arthropod assaults. Evidence exists that mosquitoes, for example, use physical, visual and
olfactory cues to locate their blood hosts,27 whereas human temperature, moisture, carbon
dioxide in the exhaled breath and body emanations are the crucial attractants.27–31 Sweat is a
major source of human volatile emissions in which carboxylic acids and Z-3-methyl-2hexenoic acid and 7-octenoic acid are key substances.32 The olfactory tissues of the insect
recognize such kairomones and info-chemicals. However, when comparing different body
regions from a naked motionless human host, the head and feet have been defined the most
preferred sites for biting because they possess a particular combination of skin temperature and
sweat gland density.33 We, therefore, suggest that the orifices of the sweat glands are preferred
by the mosquitoes. Regarding the further involvement of the lower part of the gland, we
assume that the intraepidermal duct and the secretory sweat gland coil both act as a penetration
pathway (canal) through which substances are transported.34 Arthropods while assaulting the
acrosyringia probably release toxic or irritating substances which diffuse further into the lumen
of the gland and the surrounding tissue, thus resulting in a persistent inflammatory reaction.
This condition can be referred to as eosinophilic hidradenitis because eosinophils are strongly
involved in the inflammatory infiltrate enveloping the gland structures.
The wedge shape of the infiltrate is considered usually a criterion of major importance in
arthropod bite reactions.3,7 It occurs probably as a consequence of the frontal assault as the
insect charges headlong at nearly a right angle into the skin. The infiltrate was wedge shaped in
35% of our specimens. Nevertheless, its diagnostic value renders mistrust as its appearance is a
rather subjective and speculative phenomenon arising from the V-form of most of the biopsy
specimens obtained. Furthermore, superficial sections or small punch biopsies do not enable
the accurate assessment of the wedge shape of the infiltrate.4
Histopathologic features of arthropod bite reactions are diverse and depend on numerous
factors. Distinction and observation of major and minor histopathologic criteria (specified
according to the relevance of their occurrence) might be of help for the evaluation of arthropod
reactions (Table 3). We provide morphologic evidence that the involvement of the adnexal
structures, particularly the acrosyringia, the sweat ducts and the coiled glands, should be
considered a new reliable diagnostic tool.
Table 3. Histopathologic criteria for arthropod bite reactions
Histopathologic clues
Epidermal spongiosis (eosinophilic spongiosis particularly)
Spongiotic infundibulitis and/or spongiotic acrosyringitis
Scale-crust with neutrophils and eosinophils
Moderately dense/dense, superficial and deep infiltrate with perivascular, periadnexal and
interstitial distribution
Extention of the infiltrate along the sweat ducts and the coiled glands
Interstitially distributed eosinophils
Involvement of the hair follicles and/or the sebaceous glands
Histopathologic criteria of minor relevance
Mild acanthosis, focal parakeratosis, scale crust, ulceration
Edema in the papillary dermis
Wedge-shaped form of the infiltrate
Extravasations of erythrocytes/swollen endothelia and/or dilated vessels
Flame figures
Neutrophils in the infiltrate and/or minor leukocytoclasia
Eosinophilic panniculitis"
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