Pathology of Hidradenitis Suppurativa
Alison Layton 4
Key points
Q HS is a follicular disease
Q Apocrine gland involvement appears to be secondary to follicular events
Q A lymphocytic infiltrate predominates in early lesions
Q Keratin expression suggests that sinus tracts are fragile
Q Keratin expression suggests that the outer root sheet may be involved in HS lesions
#ONTENTS
4.1 Introduction . . . 25
4.2 Glandular Elements of the Skin . . . .26
4.2.1 Sebaceous Glands and the Pilosebaceous Unit . . . .26
4.2.2 Apocrine Glands . . . 27
4.2.3 Eccrine Glands . . . 27
4.2.4 Apoeccrine Glands . . . 27
4.3 Histological Appearance of HS . . . 27
4.3.1 Early Lesions . . . 27
4.3.2 Established Hidradenitis Suppurativa . . 28
4.4 Immunohistochemistry of Hidradenitis Suppurativa . . . .30
4.5 Cytokeratin Expression in HS . . . .30
4.6 Comparison with Other Disorders . . . 31
4.6.1 Fox–Fordyce Disease . . . 31
4.6.2 Acne . . . 31
4.6.3 Follicular Occlusion Triad . . . 31
4.6.4 Pilonidal Sinus . . . 31
4.6.5 Crohn’s Disease . . . 32
4.7 Conclusions . . . 32
Acknowledgements . . . 33
References . . . 33
4.1 Introduction
There has been significant debate around the pathological features of hidradenitis suppurati- va (HS) over the years. This debate focuses on whether the primary event relates to an inflam- matory process of the apocrine duct or whether follicular occlusion is integral to the initiating process.
HS was first described as a distinct clinical entity in 1839 by Velpeau [1]. In 1854 Verneuil suggested that the inflammatory changes which affected skin of the axillae, sub-mammary/
mammary regions (Fig. 4.1) and perianal areas were linked directly to a disease of the sweat glands [2]. In 1922 a direct association was made between HS and the apocrine glands [3]. As a result of the anatomical distribution and the inflammatory changes noted, the term “apo- crinitis” was used as a synonym for HS. This terminology was supported when Brunsting demonstrated the presence of distended apo- crine glands containing polymorph neutrophils in the subcutis sections from 16 cases of estab- lished HS. He concluded that the disease was an infection that entered the hair follicle duct and expressed its full inflammatory effect within apocrine glands, with further progression oc- curring via the subcutaneous lymphatic chan- nels [4]. This explanation of pathogenesis was considered the explanation for the increased frequency of HS in African Americans, who have more apocrine glands per unit area of skin.
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However, in 1955 Shelley and Cahn applied belladonna-impregnated occlusive tape to de- pilated axillary skin in 12 healthy male volun- teers. They produced typical lesions of HS in 3 out of the 12 cases at the sites of application of the adhesive tape. The histological inflamma- tion was confined to the apocrine glands [5].
This work introduced the concept that the initi- ating event in HS relates to follicular occlusion followed by involvement of the apocrine gland.
In 1990, Yu and Cook retrospectively examined axillary skin from 12 patients with established HS [6]. Of the 12 cases, 10 showed squamous- epithelium-lined cysts or sinuses in the dermis all containing keratin and half contained hair shafts, suggesting they were derived from hair follicles. Only 4 of the cases had apocrine in- flammation and when apparent this was evident around eccrine glands, hair follicles and epithe- lium-lined structures. This work suggested that follicular occlusion was a more constant diag- nostic feature than inflammation around the apocrine glands.
A further retrospective pathological study of 118 skin specimens from 110 patients suffering from HS demonstrated that follicular occlusion
was evident in all of the specimens regardless of disease duration, which ranged from 1 month to 18 years. In contrast, control specimens from axillary and inguinal regions did not demon- strate any follicular occlusion [7]. In the same study, active folliculitis was associated with apocrinitis and apocrine destruction whereas apoeccrine glands, which drain directly onto the epidermal surface, remained intact and showed no evidence of inflammation. This work provided clear evidence that follicular occlusion by keratinous material, with subsequent active folliculitis and secondary destruction of the skin adnexae and subcutis, occurs as an integral step in the pathogenesis of HS.
A further study examining early lesions has confirmed that keratin plugging of follicles and sinuses and inflammation around the hair fol- licle are frequent features in HS [8]. Clinical support for follicular occlusion includes typical, large, multiple and grouped comedones evident in HS in apocrine sites [9, 10].
Hence, it is now believed that HS conforms to a disorder of terminal follicular epithelium within apocrine-gland-bearing skin but that apocrine involvement does not appear to be a primary event in the majority of cases [11].
4.2 Glandular Elements of the Skin The cutaneous glands in humans include holo- crine or sebaceous glands and merocrine or sweat glands. Merocrine glands are subdivided into apocrine and eccrine glands.
4.2.1 Sebaceous Glands
and the Pilosebaceous Unit The sebaceous glands are an integral part of the pilosebaceous unit and are found over the entire body surface with the exception of the palms and soles. The gland itself is made up of several lobules, which are separated by vascular con- nective tissue. These lobules all empty into a short duct which then empties into the upper part of a hair follicle at the level of the infun- dibulum. More than one sebaceous duct may drain into the upper part of the hair follicle.
Fig. 4.1. Chronic hidradenitis suppurativa of the axilla
The hair follicle, the hair, the sebaceous gland and arrectores pilorum muscle and (in certain regions) the apocrine glands make up the pilo- sebaceous unit (Fig. 4.2).
4.2.2 Apocrine Glands
Apocrine glands are found predominantly in the axillary and anogenital regions, although they are also found in the ear canal (ceruminal glands) and eyelids (Moll’s glands). They are derived from epidermis and develop as an out- growth of follicular epithelium. They represent compound sweat glands with a secretory coil that extends deep through the dermis into sub- cutaneous tissue and drains via a long straight secretory duct, usually into a hair follicle. The function of apocrine glands in humans is not altogether clear but in other mammals they are responsible for sexual attraction, and scent pro- duction is responsible for axillary and inguinal odour. They become functionally active and larger at puberty. The secretion is opalescent and malodorous.
4.2.3 Eccrine Glands
Eccrine glands are derived from a specialized down-growth of the epidermis in utero. They represent small tubular structures that drain di- rectly onto the skin surface. They exhibit ther- moregulatory control when the body is exposed to a warm environment or during heavy exer- cise. They are found in all sites of the skin ex- cluding mucous membranes. The sites of maxi- mum concentration are the palms, soles, axillae and forehead.
4.2.4 Apoeccrine Glands
These represent axillary glands in adults and combine morphological features of both eccrine and apocrine glands. A straight intradermal duct opens directly onto the skin surface. The deep secretory component conforms to a dilated apocrine segment whilst proximally the epithe- lium is compatible with an eccrine derivation.
4.3 Histological Appearance of HS
4.3.1 Early Lesions (Fig. 4.3 a–d)
Follicular hyperkeratosis with plugging and dilatation of the hair follicle is seen as an early event in HS. The follicular epithelium may pro- liferate or may be destroyed. Inflammation is frequently not apparent in early lesions but peri- folliculitis will ensue and the inflammatory in- filtrate embraces neutrophils, lymphocytes and histiocytes. Early lesions may show acute in- flammation involving the apocrine gland and duct but this is not always apparent and would appear to be a rare primary event [7]. In a study of 36 patients apocrinitis was present in only 5%
[11].
Rupture of the follicle spills its contents, in- cluding keratin and bacteria, into the surround- ing dermis [12].
Fig. 4.2. Diagrammatic representation of the piloseba- ceous unit
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4.3.2 Established Hidradenitis Suppurativa (Fig. 4.4 a–e)
Biopsy samples from established HS lesions show sinus tracts with marked suppuration and frank abscess formation. The sinuses are lined by stratified epithelium and are surrounded by fibrosis and inflammation. The squamous epi- thelium extends from the associated follicular epithelium. The inflamed sinus tracts frequent- ly contain desquamated keratin and hair shafts within the dense fibrosis [6]. Within the adja- cent connective tissue there is frequently a dense chronic inflammatory infiltrate, which contains
histiocytes and giant cells that may be related to keratin fragments. Granulation tissue with in- flammatory cells and occasional foreign body giant cells is present in 25% of biopsy specimens [13]. Apocrine glands are generally absent in the affected area but may appear quite normal in adjacent tissue. Extensive fibrosis is frequently seen as a late result in the disease course [14].
Hence it would appear that the involvement of the apocrine as well as eccrine glands repre- sents a secondary phenomenon in HS and re- sults from the inflammatory problem in deep structures.
Fig. 4.3 a–d. Early lesions in hidradenitis suppurativa. a Acute HS – lower power. b Follicular plugging. c Folliculitis – dense collection of neutrophils around hair follicle. d Acute folliculitis in HS
Fig. 4.4 a–e. Histological changes in established HS.
aChronic folliculitis – dense lymphocytic infiltrate around hair follicle. b(i) Acute and chronic inflam- matory cells around apocrine glands – low power.
(ii) Acute and chronic inflammatory cells around apocrine glands – high power. cPus in follicle.
dSinus tract formation. eScarring around hair follicle
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4.4 Immunohistochemistry of Hidradenitis Suppurativa Immunohistochemical evaluation of apocrine and eccrine involvement in HS has been per- formed retrospectively on sections of HS from vulval skin. Markers of apocrine differentiation (GCDFP-15, CD15, lysozyme) and eccrine differentiation (GCDFP-15, S-100, CA-19.9, HMB45) were used.
In total 13 cases were examined; the majority of glands identified in the samples from vulval skin were eccrine. Apocrine glands were either not seen or were present away from the area of active inflammation in 10 of the 13 cases. In 2 cases the inflammatory process had apparently destroyed all glands. Follicular obstruction was evident in 11 of the 13 cases. The inflammatory component varied, being severe in some cases to minimal in burnt-out disease. When present, inflammation of glands was only evident in association with poral occlusion, suggesting this was a secondary phenomenon. Fibrosis appeared to correlate with more chronic disease [15].
In a study looking at acute lesions of HS, im- munohistochemical examination showed a pat- tern of lymphocytic predominance suggestive of a cell-mediated response characterized by CD4 helper cells (Fig. 4.5) expressing HLA-DR positivity in keeping with an activated state (personal communication, Dr Julian Barth).
The T-helper-to-suppressor ratio was high in the acute HS lesions and in keeping with a cell- mediated response.
These changes mirror those found in experi- mentally induced early acne lesions [16] where a high ratio of T4 to T8 cells was found at 24 h.
Further work looking at time-coursed biopsy samples in acne also confirmed these findings [17].
These identical results in early HS and acne lesions suggest there may be a common mecha- nism with a type-IV delayed hypersensitivity response to an as yet unidentified antigen.
4.5 Cytokeratin Expression in HS Cytokeratin (CK) is an important marker for evaluating the origin and state of differentiation of epithelial cells. CK17 (found in normal in- fundibulum, Fig. 4.6) has been shown to be ab- sent from infundibular-like keratinized epithe- lium from HS lesions. This suggests fragility of the draining sinus epithelial, which may allow rupture to occur more easily, thus resulting in a subcutaneous abscess. Keratin expression in non-infundibular keratinized and non-keratin- ized epithelium of HS lesions has been shown to be similar to that observed in the outer root sheath in normal hair follicles [18]. Hence drain- ing sinus epithelium in HS may possess charac- teristics of undifferentiation and hyperprolifer- ation.
Fig. 4.5. CD4 cells around the follicular duct
Fig. 4.6. Normal pilosebaceous unit, CK17 was present in suprabasal layers of the infundibulum (original mag- nification =100)
4.6 Comparison
with Other Disorders 4.6.1 Fox–Fordyce Disease
Fox–Fordyce disease has the same anatomical distribution, as well as age and sex incidence as HS. This condition is more convincingly associ- ated with an inflammatory process of the apo- crine duct. Of interest there have been descrip- tions of some cases of Fox–Fordyce disease progressing to HS.
4.6.2 Acne
The pathogenesis of acne embraces increased sebum production, follicular hyperkeratosis, colonization with propionibacteria and inflam- matory changes. The sebaceous duct hyperkera- tinization is mediated by the production of in- terleukin-1 alpha (IL1-A) and tumour necrosis factor alpha (TNF-A) by keratinocytes and T- lymphocytes. The result is hyperproliferation of keratinocytes, reduced apoptosis and conse- quent hypergranulosis. As a result the sebaceous follicle becomes blocked with densely packed keratin and so evolves the comedo. Early come- dones show a dilated hair follicle associated with infundibular hyperkeratosis. Later due to rup- ture an acute dermal inflammatory response ensues. This can be complicated by a foreign body granulomatous reaction. In severe cases abscesses frequently present and cysts and si- nuses form. Dermal scarring frequently results in these cases.
4.6.3 Follicular Occlusion Triad In 1956, Pillsbury, Shelley and Kligman coined the term follicular occlusion triad for the com- mon association of acne conglobata, HS and dissecting folliculitis of the scalp. They pro- posed that the pathological event unique to each disease was follicular hyperkeratinization [19].
All three diseases, HS, acne conglobata and dissecting folliculitis, represent chronic, recur- rent deep-seated folliculitis resulting in abscess- es followed by sinus tract formation and scar- ring. In an actively inflamed lesion the sinus contains hairs surrounded by neutrophils, gran- ulation and scar tissue (Fig. 4.7). In an end-stage lesion there is scarring with patchy inflamma- tion, which may track down a healed sinus at the site of a destroyed hair follicle.
The key histological features of all these con- ditions are:
1. Poral occlusion of the pilosebaceous units within intertriginous skin sites, especially the axillary area and anogenital regions 2. Secondary inflammation of apocrine
glands
3. Inflamed nodules and sterile abscesses, which are followed by sinus tracts, fistulae and hypertrophic scars.
4.6.4 Pilonidal Sinus
In 1975 pilonidal sinus (PS) was reported to be- long to the category of follicular occlusion dis- eases so creating the follicular tetrad [20]. His- topathological findings in PS show follicular
Fig. 4.7. Dissecting folliculitis of the scalp
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hyperkeratosis of the infundibulum with plug- ging and dilatation of the follicle (Fig. 4.8). Su- perficially the sinus is often lined with stratified squamous epithelium but towards the deeper reaches the wall consists of granulation and scar tissue. The early inflammatory event is perifol- liculitis with neutrophils, lymphocytes and his- tiocytes leading to rupture of follicular epithe- lium.
In a recent study using immunohistochemis- try with six antikeratin antibodies it has been demonstrated that CK expression in PS is simi- lar to that in HS, suggesting that the epithelium may be fragile, hyperproliferative and undiffer-
entiated [21]. Infundibular-like epithelium con- tained CK1, CK10 and CK14, similar to normal infundibulum, but CK17 was absent (Fig. 4.9).
4.6.5 Crohn’s Disease
Differentiating HS from Crohn’s disease merits attention. At times these diseases can be clini- cally indistinguishable and authors have em- phasized that although foreign body granulo- mas are a common finding in HS, the presence of discrete epithelioid granulomas in the dermis away from the site of active inflammation is un- usual and should alert the pathologist to the possibility of systemic granulomatous disease such as Crohn’s or sarcoidosis [22]. Several authors have reported the co-morbidity of HS and Crohn’s [23] (see Fig. 4.10).
4.7 Conclusions
W
The histological spectrum of HS is broad. The disease appears to be predominantly follicu- lar and apocrine glands appear to be primarily involved in only a minority of histological specimens. Although inflammation does not appear to originate within the apocrine glands, the exclusive finding of the disease within apocrine-gland-bearing skin indicates Fig. 4.8. Pilonidal sinus
Fig. 4.9. Pilonidal sinus – CK17 was absent in type A epithelium (original magnification =100)
Fig. 4.10. Crohn’s disease with epithelioid granulomas
an apocrine effect. This diversity of pathologi- cal presentation may well explain the thera- peutic challenge that this condition poses.
Acknowledgements
I would like to acknowledge the following peo- ple:
Professor I Kurokawa, Department of Der- matology, Hyogo Prefectural Hospital, Japan, for providing me with and permitting me to in- clude information and slides on the immuno- histochemistry of HS and PS.
Dr Anne Gledhill, Department of Pathology, Harrogate and District Foundation Trust, UK and Dr S Edwards Department of Pathology, Leeds Teaching Hospital, UK, for providing his- tological sections of HS and related diseases.
Dr Julian Barth, Department of Chemical Pathology, Leeds Teaching Hospital, UK, for providing valuable advice and information on HS.
Dr Anthony Yung, Department of Dermatol- ogy, Leeds Teaching Hospital, UK
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