Download Rosacea under the microscope: characteristic histological findings

JEADV
DOI: 10.1111/jdv.12121
REVIEW ARTICLE
Rosacea under the microscope: characteristic histological
findings
B. Cribier*
Clinique Dermatologique, University Hospital, Strasbourg, France
*Correspondence: B. Cribier. E-mail: [email protected]
Abstract
Rosacea is a common facial dermatosis that is seldom biopsied; thus, histological aspects have not been well described.
Biopsies are generally performed in the presence of atypical symptoms (e.g. granulomas). Differential diagnosis with sarcoidosis, lupus miliaris or lupus erythematosus is another indication for biopsy. There are few published studies addressing the microscopic aspects of rosacea and describing the histological and immunohistochemical features of this
disease. While some textbooks consider the microscopic signs of rosacea to be non-diagnostic, experienced dermatopathologists are generally able to make the diagnosis via histology. This article discusses the specific combinations of
histological features that are highly suggestive of rosacea.
Received: 18 June 2012; Accepted: 28 January 2013
Conflict of interest
ne, Intendis); clinical trial (BiorgaConsultant (Galderma International); invited speaker (Galderma, Pierre Fabre, Ave
Bailleul)
Introduction
Rosacea manifests in a variety of clinical presentations. Facial
redness may be accompanied by papules and/or pustules, and
in some cases, ocular involvement or phymatous changes.
The condition encompasses a range of pathologic mechanisms
that are relatively poorly understood, although most researchers now agree that the pathophysiology involves two primary
factors: vascular abnormalities and inflammation. It has
recently been proposed that innate immune mechanisms and
changes in regulation of the neurovascular system come
together to initiate and perpetuate rosacea, although the exact
mechanisms and corresponding reactions have yet to be
elucidated.1
A full discussion of rosacea pathophysiology is beyond the
scope of this article, but mention of several factors may be helpful when considering the histological manifestations of the disease. Environmental triggers such as sunlight exposure and
temperature change are thought to play a part in disease pathophysiology by contributing to vascular changes in susceptible
individuals. Vascular abnormalities result in blood vessel dilation with increased capillary permeability and oedema, which in
turn provide a favourable setting for Demodex colonization and
proliferation. Demodex stimulates inflammation, increasing the
likelihood of papulo-pustular or granulomatous lesions. Additional inflammatory actions, including the release of oxygen free
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radicals, also contribute to dermal and blood vessel damage. As
an example, altered innate immune activity can result in overexpression of pro-inflammatory peptides such as cathelicidin. As is
the case in other skin conditions, dermatopathology can provide
valuable information that can help to understand the various
mechanisms of rosacea. Both inflammatory infiltrate and vascular changes can be easily observed, characterized and quantified
under the microscope, using routine staining and immunohistochemistry.
Biopsy is rarely performed for rosacea in routine clinical
practice, as the primary accepted diagnostic features of rosacea are clinical.2,3 Yet biopsy may help where symptoms are
atypical or when the differential diagnosis remains unclear.
Recently, the author performed a large clinicopathologic
study that included collecting biopsies from patients with
dermatologist-diagnosed rosacea (N = 86).4,5 Biopsies were
performed by a dermatologist, who also collected information
about clinical disease presentation. Histological examinations
included haematoxylin and eosin staining and evaluation of
cutaneous changes. Immunohistochemical analyses were performed along with inflammatory infiltrate typing.5 From these
data and other published data, the main histological features
of rosacea were identified (summarized in Table 1). It is
hoped this article will show that histological markers can be
quite useful in diagnosis of rosacea.
© 2013 The Author
Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology
Rosacea under the microscope
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Table 1 Histological features of rosacea: summary (2)
Abnormality
Characteristics in Rosacea
Extensive telangiectasias throughout
the superficial and middle dermis
● Enlarged lumen
● Unusual shape (tortuous or geometric contours, intraluminal projections), number and size of
telangiectatic vessels
● Relatively low number of endothelial cells
Perivascular infiltrate
● Surrounds dilated vessels
● Characteristically present at a moderate level
● Composed of mononuclear cells (lymphocytes, histiocytes, plasma cells)
Oedema of superficial dermis
● Visualized as lucent band in superficial papillary and reticular dermis
● Little or no mucin in empty spaces
● Accompanied by inflammatory infiltrate
Increased dermal mast cells
● Accompany the enlarged blood vessels
● May play a role in neoangiogenesis
Table 2 Histological features of Erythemato-telangiectatic rosacea (ETR) subtype of rosacea
● Enlarged, dilated capillaries and venules in upper dermis
○ Frequently have bizarre shapes
● Presence of Demodex mites
● Oedema in upper dermis
● Lymphocytic inflammation of varying degrees
● Spongiosis (common, but not specific to rosacea)
● No changes in dermo-epidermal junction
Table 3 Histological features of papulo-pustular rosacea (PPR)
subtype of rosacea
● Conspicuous superficial and deep inflammation
○ Mixed infiltrate
○ Eosinophils plus plasma cells
● Presence of Demodex mites
● Spongiosis, exocytosis and acute folliculitis are common
● Solar elastosis
● Absence of retentional elements such as dermal infundibular cysts
Table 4 Histological features of granulomatous rosacea
Figure 1 Diffuse Erythemato-telangiectatic rosacea (ETR).
● Large granulomas in the superficial and mid dermis
○ Large central empty space
○ Can also be small palisaded, elastolytic or diffuse
● Demodex mites and sometimes remnants of mites
● No caseation
Erythemato-telangiectatic rosacea
Erythemato-telangiectatic rosacea (ETR) (Fig 1) is a common
rosacea subtype with clinical characteristics that include flushing, central facial erythema and telangiectasias.6,7 Microscopic
examination of ETR biopsies typically shows non-specific
features, but one important characteristic change is the presence
of enlarged, dilated capillaries and venules located in the upper
part of the dermis (Fig 2). Most cases also exhibit the telltale
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presence of Demodex within the follicular infundibulum, even in
the absence of papules or pustules (Fig 3).
The enlarged vessels, mostly capillaries, often exhibit a
bizarre shape (Fig 4), with few visible endothelial cells.4,8
Immunohistochemistry demonstrates that such vessels express
CD31 but not D2-40, a marker of lymphatic vessels. In rosacea,
D2-40 positive vessels (Fig 5) are, in the author’s experience,
small and located in the upper and mid dermis. Thus, the number of lymphatic vessels remains relatively normal.4
A typical, angulated telangiectasias and mild lymphocytic
infiltrate are the hallmarks of early ETR. Mild to moderate
oedema, almost always present on histology, is responsible for
the clear aspect of the upper dermis and may be due to increased
© 2013 The Author
Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology
Cribier
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Figure 2 Biopsy of Erythemato-telangiectatic rosacea (ETR) subtype, showing dilated superficial vessels with prominent endothelial cells and oedema of the upper dermis. Also noteworthy are
spongiosis and lymphocyte exocytosis within the epidermis.
Figure 4 Characteristic bizarre shaped, enlarged venules and
capillaries in biopsy of vascular rosacea.
Figure 3 Case of Erythemato-telangiectatic rosacea (ETR) with
Demodex present.
Figure 5 Erythemato-telangiectatic rosacea (ETR) stain with
D2-40 antibodies on small vessels but not large.
number of vessels and defective permeability as well as the
discontinuity of endothelial cells.3,8 Oedema in rosacea is rarely
visible to the naked eye, with the exception of solid facial
oedema.4,9
The inflammatory infiltrate is mainly composed of lymphocytes with a few histiocytes also present.10 The lymphocytic infiltrate is composed of a predominant CD3 + T-cell population
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© 2013 The Author
Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology
Rosacea under the microscope
(at least 70% to 80%) and a minority of CD20 + B cells (10% to
20%). T lymphocytes appear mainly as CD4 + , with a minor
CD8 + population (<30%) (unpublished personal results). Mast
cells are increased in number.11 Plasma cells are frequently seen
and are an important clue to disease diagnosis.
Inflammation typically occurs throughout the upper, mid and
deep dermis, but in macular lesions is localized in the upper dermis (Table 2). The density of the inflammatory infiltrate varies
between individuals and can also vary over time. The prerequisite inflammatory background in ETR subtype is both perivascular and interstitial. Spongiotic dermatitis is common but not
specific to rosacea. When slightly elevated plaques are present,
the infiltrate density around the capillaries and venules of the
upper dermis becomes important. Here, biopsy is indicated to
rule out lupus erythematosus (LE). In the case of LE, the infiltrate is perivascular and perifollicular and there are changes in
the dermo-epidermal junction (e.g. vacuolization of basal keratinocytes and thickening of the basal membrane) which are not
observed in rosacea.
Papulo-pustular rosacea
In papulo-pustular rosacea (PPR), central facial erythema is
characteristic and accompanied by transient papules, pustules or
both.7 Comedones are absent, unless the patient has
concomitant acne vulgaris; telangiectasias may be present.7 Histologically, PPR is characterized by mixed inflammatory infil-
(a)
(c)
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trate, with numerous plasma cells, neutrophils and sometimes
eosinophils (Fig 6).10,12 When papular or pustular lesions are
present, inflammation is much more conspicuous on histology
compared with other rosacea subtypes; further, inflammation is
typically present in both superficial and deep skin layers. Mast
cell count is increased in lesional skin, however, the quantities of
mast cells are not well correlated with either severity or duration
of the disease.11 The main diagnostic sign that helps to differentiate rosacea from acne is the absence of retentional elements,
i.e. comedones and dermal infundibular cysts.
The follicular or extrafollicular nature of pustules is debated,
and histology shows that while pustules primarily involve the
follicle there may also be some involvement outside of the
follicle (Table 3).13 Specifically, while the infiltrate is generally
perifollicular,10,11 small extrafollicular abscesses might aso be
observed. Unlike in folliculitis, neutrophil collections are located
around the infundibula, and often correlate with the presence of
D. mites (Fig 7). Demodex are almost always present in histological samples from individuals with PPR. Spongiosis and exocytosis are common in the adjacent epidermis. Ruptured follicles are
surrounded by a denser infiltrate and the histological images are
similar to those seen in acne. When papular lesions are examined histologically, a perifollicular lymphocytic infiltrate is typically present.
Solar elastosis is also a typical histological finding even
if not clinically apparent. Its presence reflects the probable
(b)
(d)
Figure 6 (a) papulo-pustular rosacea (PPR) biopsy with a large collection of neutrophils beside the follicle on the left, superficial oedema,
dense lymphocytic inflammation and dilated vessels. (b) Superficial collection of neutrophils, eosinophilic debris and ruptured infundibulum in a biopsy of pustular rosacea. (c) Biopsy with prominent pustule. (d) Pustule with collection of neutrophils and Demodex located
outside of the follicle.
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eral histiocytes admixed with lymphocytes.15,16 Serial sections
often show D. mites or eosinophilic remnants of Demodex in
the centre of histiocyte collections (Fig 8); both findings
strengthen theories of Demodex involvement in this subtype.17
Other types of granulomas can be observed, i.e. small palisaded, elastolytic or more diffuse granulomas. In certain cases,
granulomas might be the sole feature of the disease, without
prominent dilated vessels (e.g. lupoid rosacea or granulomatous
perioral dermatitis).
Phymatous rosacea
pathophysiological role of ultraviolet (UV) exposure and associated free radical damage in rosacea.4
Phymatous rosacea often involves the nose and includes thickened skin, irregular surface nodularities and hypertrophy
(Fig 9).7 Telangiectasias and patulous, expressive follicles in the
area of the phyma are sometimes visible; the signs and symptoms of ETR and PPR may also be present (Table 4).7 Histologically, rhinophyma is characterized by increased volume of
sebaceous glands and fibrosis (Fig 10).18 The sebaceous lobules
are extremely large, as in senile sebaceous hyperplasia, but the
structure of the gland is normal. The infundibula are enlarged
and filled with lamellar keratin, eosinophilic debris and microorganisms.19 Demodex mites are common.
Enlargement of infundibula is associated with the formation
of epidermal cysts that can rupture and induce inflammation.
Inflammation is always present, but is generally less conspicuous
than in PPR. The infiltrate is mainly lymphocytes and neutrophils around the enlarged infundibula. Small granulomas might
also be present.
Granulomatous rosacea
Variants in clinical practice
Figure 7 Pustular rosacea with remnants of Demodex within the
neutrophil infiltrate.
Granulomas are commonly observed in rosacea,14 and are
not restricted to the centrofacial area.15 The lesions are typically hard, red–brown to yellow papules that are found in a
symmetrical distribution.15 Histologically, granulomatous
rosacea is characterized by large granulomas of the superficial
and mid dermis that can include a large, central empty space
surrounded by a layer of neutrophils and numerous periph-
(a)
Demodicosis
Demodicosis is a broad term applied to skin conditions due
to D. mites, including several variants that are clinically
similar to rosacea.20 In the author’s experience, it is not
possible to differentiate rosacea from demodicosis based on
histopathological analysis. In severe cases with scaling,
(b)
Figure 8 (a) Clinical presentations of granulomatous rosacea. (b) Histology of granulomatous rosacea.
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Rosacea under the microscope
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Figure 9 Rhinophyma.
parakeratosis with numerous neutrophils can be seen at the
surface of pustular lesions.
Figure 11 Rosacea with seborrhoeic dermatitis.
Seborrhoeic dermatitis/rosacea
Certain cases of rosacea exhibit distinct signs of seborrhoeic
dermatitis (Fig 11,12).21 In these cases, histopathology shows
mixed features, i.e. dilated superficial vessels (a feature not present in classic seborrhoeic dermatitis), oedema and perivascular/
perifollicular infiltrate associated with foci of parakeratosis. PAS
staining can show Malassezia yeasts.21
(a)
Summary
Rosacea has a multifactorial pathology that includes both
inflammatory processes and a prominent vascular component.
On histology, characteristic components include enlarged and
strangely shaped small blood vessels, and perivascular and interstitial inflammation. Oedema is often present and visible.
(b)
(c)
Figure 10 (a) Enlarged sebaceous glands and peripheral fibrosis in biopsy of rhinophyma (hypertrophic rosacea), (b) rhinophyma biopsy
with large cystic space, (c) rhinophyma with fibrosis and dilated vessels at top.
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(a)
(b)
Figure 12 (a) Biopsy showing Demodex mite, thick parakeratosis and inflammation, (b) parakeratosis containing neutrophils and dense
lymphocytic infiltrate.
Granulomas are also common and may be associated with elastosis.14,22
There is a high rate of Demodex carriage in all clinical subtypes of rosacea.5 Because the mite is present in >60% of ETR, it
may have a role in stimulating inflammation via its resident bacteria or proteins from bacterial degradation.5
It is possible that the vascular abnormalities of rosacea, primarily in capillaries, are a form of photodamage.23 The changes
in size and shape of small blood vessels in rosacea may explain a
lack of permeability that leads to oedema, which is usually visible
on histology and often associated with spongiotic skin alterations.5 The association between vascular changes and inflammation remains unclear, but identification of pro-inflammatory
mechanisms of innate immunity in rosacea may help explain
formation of telangiectasia in the papulo-pustular form of the
disease.5 In addition, the confluence of vasodilation plus
increased blood flow and higher local temperature may encourage colonization and proliferation of Demodex.5 Finally, it seems
likely that the subjective signs and symptoms of rosacea may be
related to the proximity of the superficial dermal vessels and
nerve fibres.5
Lymphocytic infiltrates can be seen, and while similar in cellular makeup with other conditions such as LE, the infiltrate is
typically less pronounced in rosacea.5 The infiltrate contains
mainly T cells, primarily CD4 + lymphocytes. Plasma cells and
eosinophils are not uncommon, suggesting an infectious reaction.5 These histological markers of rosacea can be quite useful
in making and excluding a diagnosis.
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© 2013 The Author
Journal of the European Academy of Dermatology and Venereology © 2013 European Academy of Dermatology and Venereology