REVIEW ARTICLE
Rosacea under the microscope: characteristic histological
fi
ndings
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 sar-coidosis, lupus miliaris or lupus erythematosus is another indication for biopsy. There are few published studies address-ing the microscopic aspects of rosacea and describaddress-ing the histological and immunohistochemical features of this disease. While some textbooks consider the microscopic signs of rosacea to be non-diagnostic, experienced dermatop-athologists 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
Consultant (Galderma International); invited speaker (Galderma, Pierre Fabre, Avene, Intendis); clinical trial (Biorga-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 research-ers 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 help-ful when considering the histological manifestations of the dis-ease. Environmental triggers such as sunlight exposure and temperature change are thought to play a part in disease patho-physiology by contributing to vascular changes in susceptible individuals. Vascular abnormalities result in blood vessel dila-tion with increased capillary permeability and oedema, which in turn provide a favourable setting forDemodexcolonization and proliferation.Demodex stimulates inflammation, increasing the likelihood of papulo-pustular or granulomatous lesions. Addi-tional inflammatory actions, including the release of oxygen free
radicals, also contribute to dermal and blood vessel damage. As an example, altered innate immune activity can result in overex-pression 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 vascu-lar changes can be easily observed, characterized and quantified under the microscope, using routine staining and immunohisto-chemistry.
Biopsy is rarely performed for rosacea in routine clinical practice, as the primary accepted diagnostic features of rosa-cea 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 per-formed 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.
Erythemato-telangiectatic rosacea
Erythemato-telangiectatic rosacea (ETR) (Fig 1) is a common rosacea subtype with clinical characteristics that include flush-ing, 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
presence ofDemodexwithin 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 num-ber 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 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 rosa-cea (ETR) subtype of rosarosa-cea
●Enlarged, dilated capillaries and venules in upper dermis
○Frequently have bizarre shapes
●Presence ofDemodexmites
●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 ofDemodexmites
●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
●Large granulomas in the superficial and mid dermis
○Large central empty space
○Can also be small palisaded, elastolytic or diffuse
●Demodexmites and sometimes remnants of mites
●No caseation
number of vessels and defective permeability as well as the discontinuity of endothelial cells.3,8Oedema 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 lympho-cytes with a few histiolympho-cytes also present.10The lymphocytic
infil-trate is composed of a predominant CD3+T-cell population Figure 3 Case of Erythemato-telangiectatic rosacea (ETR) with
Demodex present.
Figure 4 Characteristic bizarre shaped, enlarged venules and capillaries in biopsy of vascular rosacea.
Figure 2 Biopsy of Erythemato-telangiectatic rosacea (ETR) sub-type, showing dilated superficial vessels with prominent endothe-lial cells and oedema of the upper dermis. Also noteworthy are spongiosis and lymphocyte exocytosis within the epidermis.
Figure 5 Erythemato-telangiectatic rosacea (ETR) stain with D2-40 antibodies on small vessels but not large.
(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.11Plasma 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 der-mis (Table 2). The density of the inflammatory infiltrate varies between individuals and can also vary over time. The prerequi-site inflammatory background in ETR subtype is both perivascu-lar 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 infil-trate is perivascular and perifollicular and there are changes in the dermo-epidermal junction (e.g. vacuolization of basal kerati-nocytes 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 His-tologically, PPR is characterized by mixed inflammatory
infil-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.11The main diagnostic sign that helps to
differen-tiate 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).13Specifically, 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).Demodexare almost always present in histolog-ical samples from individuals with PPR. Spongiosis and exocyto-sis 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 exam-ined histologically, a perifollicular lymphocytic infiltrate is typi-cally present.
Solar elastosis is also a typical histological finding even if not clinically apparent. Its presence reflects the probable
(a) (b)
(c) (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 infundibu-lum in a biopsy of pustular rosacea. (c) Biopsy with prominent pustule. (d) Pustule with collection of neutrophils andDemodexlocated outside of the follicle.
pathophysiological role of ultraviolet (UV) exposure and associ-ated free radical damage in rosacea.4
Granulomatous rosacea
Granulomas are commonly observed in rosacea,14 and are not restricted to the centrofacial area.15 The lesions are typi-cally 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-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 sub-type.17
Other types of granulomas can be observed, i.e. small pali-saded, 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
Phymatous rosacea often involves the nose and includes thick-ened skin, irregular surface nodularities and hypertrophy (Fig 9).7Telangiectasias and patulous, expressive follicles in the area of the phyma are sometimes visible; the signs and symp-toms of ETR and PPR may also be present (Table 4).7 Histologi-cally, rhinophyma is characterized by increased volume of sebaceous glands and fibrosis (Fig 10).18The 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 microor-ganisms.19Demodexmites 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 neutroph-ils around the enlarged infundibula. Small granulomas might also be present.
Variants in clinical practice 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, Figure 7 Pustular rosacea with remnants ofDemodexwithin the
neutrophil infiltrate.
(a) (b)
parakeratosis with numerous neutrophils can be seen at the surface of pustular lesions.
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 pres-ent in classic seborrhoeic dermatitis), oedema and perivascular/ perifollicular infiltrate associated with foci of parakeratosis. PAS staining can showMalasseziayeasts.21
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 inter-stitial inflammation. Oedema is often present and visible. Figure 9 Rhinophyma.
(a)
(c)
(b)
Figure 10 (a) Enlarged sebaceous glands and peripheralfibrosis in biopsy of rhinophyma (hypertrophic rosacea), (b) rhinophyma biopsy with large cystic space, (c) rhinophyma withfibrosis and dilated vessels at top.
Granulomas are also common and may be associated with elas-tosis.14,22
There is a high rate ofDemodex carriage in all clinical sub-types of rosacea.5Because the mite is present in>60% of ETR, it may have a role in stimulating inflammation via its resident bac-teria or proteins from bacbac-terial degradation.5
It is possible that the vascular abnormalities of rosacea, pri-marily in capillaries, are a form of photodamage.23The 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 altera-tions.5The association between vascular changes and
inflamma-tion remains unclear, but identificainflamma-tion 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 encour-age colonization and proliferation ofDemodex.5Finally, 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 cellu-lar 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 reac-tion.5These histological markers of rosacea can be quite useful
in making and excluding a diagnosis. References
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