Chapter 4 Pathology of Suppurativa 4 Alison Layton

4.7 Conclusions ...... 32 Key points Acknowledgements ...... 33 Q HS is a follicular disease References ...... 33

Q gland involvement appears to be secondary to follicular events 4.1 Introduction

Q A lymphocytic infiltrate predominates There has been significant debate around the in early lesions pathological features of hidradenitis suppurati- va (HS) over the years. This debate focuses on Q expression suggests that sinus whether the primary event relates to an inflam- tracts are fragile matory process of the apocrine duct or whether follicular occlusion is integral to the initiating Q Keratin expression suggests that the process. outer root sheet may be involved HS was first described as a distinct clinical in HS lesions 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 #ONTENTS were linked directly to a disease of the sweat 4.1 Introduction ...... 25 glands [2]. In 1922 a direct association was made between HS and the apocrine glands [3]. As a 4.2 Glandular Elements of the Skin ...... 26 result of the anatomical distribution and the 4.2.1 Sebaceous Glands and the Pilosebaceous Unit ...... 26 inflammatory changes noted, the term “apo- 4.2.2 Apocrine Glands ...... 27 crinitis” was used as a synonym for HS. This 4.2.3 Eccrine Glands ...... 27 terminology was supported when Brunsting 4.2.4 Apoeccrine Glands ...... 27 demonstrated the presence of distended apo- 4.3 HistologicalAppearanceofHS ...... 27 crine glands containing polymorph neutrophils 4.3.1 Early Lesions ...... 27 in the subcutis sections from 16 cases of estab- 4.3.2 Established ..28 lished HS. He concluded that the disease was an 4.4 Immunohistochemistry that entered the follicle duct and of Hidradenitis Suppurativa ...... 30 expressed its full inflammatory effect within 4.5 Cytokeratin Expression in HS ...... 30 apocrine glands, with further progression oc- curring via the subcutaneous lymphatic chan- 4.6 Comparison with Other Disorders ...... 31 nels [4]. This explanation of pathogenesis was 4.6.1 Fox–Fordyce Disease ...... 31 4.6.2 ...... 31 considered the explanation for the increased 4.6.3 Follicular Occlusion Triad ...... 31 frequency of HS in African Americans, who 4.6.4 Pilonidal Sinus ...... 31 have more apocrine glands per unit area of 4.6.5 Crohn’s Disease ...... 32 skin. 26 Alison Layton

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 was associated with apocrinitis and apocrine destruction whereas apoeccrine glands, which drain directly onto the epidermal surface, remained intact and 4 showed no evidence of . 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 Fig. 4.1. Chronic hidradenitis suppurativa of the in HS in apocrine sites [9, 10]. Hence, it is now believed that HS conforms to a disorder of terminal follicular However, in 1955 Shelley and Cahn applied within apocrine-gland-bearing skin but that belladonna-impregnated occlusive tape to de- apocrine involvement does not appear to be a pilated axillary skin in 12 healthy male volun- primary event in the majority of cases [11]. 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- 4.2 Glandular Elements of the Skin tion was confined to the apocrine glands [5]. This work introduced the concept that the initi- The cutaneous glands in humans include holo- ating event in HS relates to follicular occlusion crine or sebaceous glands and merocrine or followed by involvement of the apocrine gland. sweat glands. Merocrine glands are subdivided In 1990, Yu and Cook retrospectively examined into apocrine and eccrine glands. axillary skin from 12 patients with established HS [6]. Of the 12 cases, 10 showed squamous- epithelium-lined or sinuses in the dermis 4.2.1 Sebaceous Glands all containing keratin and half contained hair and the Pilosebaceous Unit shafts, suggesting they were derived from hair follicles. Only 4 of the cases had apocrine in- The sebaceous glands are an integral part of the flammation and when apparent this was evident pilosebaceous unit and are found over the entire around eccrine glands, hair follicles and epithe- body surface with the exception of the palms lium-lined structures. This work suggested that and soles. The gland itself is made up of several follicular occlusion was a more constant diag- lobules, which are separated by vascular con- nostic feature than inflammation around the nective tissue. These lobules all empty into a apocrine glands. short duct which then empties into the upper A further retrospective pathological study of part of a at the level of the infun- 118 skin specimens from 110 patients suffering dibulum. More than one sebaceous duct may from HS demonstrated that follicular occlusion drain into the upper part of the hair follicle. Pathology of Hidradenitis Suppurativa Chapter 4 27

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 Fig. 4.2. Diagrammatic representation of the piloseba- and apocrine glands. A straight intradermal ceous unit duct opens directly onto the skin surface. The deep secretory component conforms to a dilated The hair follicle, the hair, the apocrine segment whilst proximally the epithe- and arrectores pilorum muscle and (in certain lium is compatible with an eccrine derivation. regions) the apocrine glands make up the pilo- sebaceous unit (Fig. 4.2). 4.3 Histological Appearance of HS

4.2.2 Apocrine Glands 4.3.1 Early Lesions (Fig. 4.3a–d)

Apocrine glands are found predominantly in Follicular with plugging and the axillary and anogenital regions, although dilatation of the hair follicle is seen as an early they are also found in the ear canal (ceruminal event in HS. The follicular epithelium may pro- glands) and eyelids (Moll’s glands). They are liferate or may be destroyed. Inflammation is derived from epidermis and develop as an out- frequently not apparent in early lesions but peri- growth of follicular epithelium. They represent folliculitis will ensue and the inflammatory in- compound sweat glands with a secretory coil filtrate embraces neutrophils, lymphocytes and that extends deep through the dermis into sub- histiocytes. Early lesions may show acute in- cutaneous tissue and drains via a long straight flammation involving the apocrine gland and secretory duct, usually into a hair follicle. The duct but this is not always apparent and would function of apocrine glands in humans is not appear to be a rare primary event [7]. In a study altogether clear but in other mammals they are of 36 patients apocrinitis was present in only 5% responsible for sexual attraction, and scent pro- [11]. duction is responsible for axillary and inguinal Rupture of the follicle spills its contents, in- odour. They become functionally active and cluding keratin and , into the surround- larger at puberty. The secretion is opalescent ing dermis [12]. and malodorous. 28 Alison Layton

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Fig. 4.3a–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

4.3.2 Established Hidradenitis histiocytes and giant cells that may be related to Suppurativa (Fig. 4.4a–e) keratin fragments. Granulation tissue with in- flammatory cells and occasional foreign body Biopsy samples from established HS lesions giant cells is present in 25% of biopsy specimens show sinus tracts with marked suppuration and [13]. Apocrine glands are generally absent in the frank formation. The sinuses are lined affected area but may appear quite normal in by stratified epithelium and are surrounded by adjacent tissue. Extensive is frequently fibrosis and inflammation. The squamous epi- seen as a late result in the disease course [14]. thelium extends from the associated follicular Hence it would appear that the involvement epithelium. The inflamed sinus tracts frequent- of the apocrine as well as eccrine glands repre- ly contain desquamated keratin and hair shafts sents a secondary phenomenon in HS and re- within the dense fibrosis [6]. Within the adja- sults from the inflammatory problem in deep cent connective tissue there is frequently a dense structures. chronic inflammatory infiltrate, which contains Pathology of Hidradenitis Suppurativa Chapter 4 29

Fig. 4.4a–e. Histological changes in established HS. a Chronic 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. c in follicle. d Sinus tract formation. e Scarring around hair follicle 30 Alison Layton

4.4 Immunohistochemistry These changes mirror those found in experi- of Hidradenitis Suppurativa mentally induced early acne lesions [16] where a high ratio of T4 to T8 cells was found at 24 h. Immunohistochemical evaluation of apocrine Further work looking at time-coursed biopsy and eccrine involvement in HS has been per- samples in acne also confirmed these findings formed retrospectively on sections of HS from [17]. vulval skin. Markers of apocrine differentiation These identical results in early HS and acne (GCDFP-15, CD15, lysozyme) and eccrine lesions suggest there may be a common mecha- differentiation (GCDFP-15, S-100, CA-19.9, nism with a type-IV delayed hypersensitivity 4 HMB45) were used. response to an as yet unidentified antigen. In total 13 cases were examined; the majority of glands identified in the samples from vulval skin were eccrine. Apocrine glands were either 4.5 Cytokeratin Expression in HS not seen or were present away from the area of active inflammation in 10 of the 13 cases. In 2 Cytokeratin (CK) is an important marker for cases the inflammatory process had apparently evaluating the origin and state of differentiation destroyed all glands. Follicular obstruction was of epithelial cells. CK17 (found in normal in- evident in 11 of the 13 cases. The inflammatory fundibulum, Fig. 4.6) has been shown to be ab- component varied, being severe in some cases to sent from infundibular-like keratinized epithe- minimal in burnt-out disease. When present, lium from HS lesions. This suggests fragility of inflammation of glands was only evident in the draining sinus epithelial, which may allow association with poral occlusion, suggesting this rupture to occur more easily, thus resulting in a was a secondary phenomenon. Fibrosis appeared subcutaneous abscess. Keratin expression in to correlate with more chronic disease [15]. non-infundibular keratinized and non-keratin- In a study looking at acute lesions of HS, im- ized epithelium of HS lesions has been shown to munohistochemical examination showed a pat- be similar to that observed in the outer root tern of lymphocytic predominance suggestive sheath in normal hair follicles [18]. Hence drain- of a -mediated response characterized by ing sinus epithelium in HS may possess charac- CD4 helper cells (Fig. 4.5) expressing HLA-DR teristics of undifferentiation and hyperprolifer- positivity in keeping with an activated state ation. (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.

Fig. 4.6. Normal pilosebaceous unit, CK17 was present in suprabasal layers of the infundibulum (original mag- Fig. 4.5. CD4 cells around the follicular duct nification =100) Pathology of Hidradenitis Suppurativa Chapter 4 31

Fig. 4.7. Dissecting folliculitis of the scalp

4.6 Comparison 4.6.3 Follicular Occlusion Triad with Other Disorders In 1956, Pillsbury, Shelley and Kligman coined 4.6.1 Fox–Fordyce Disease the term follicular occlusion triad for the com- mon association of , HS and Fox–Fordyce disease has the same anatomical dissecting folliculitis of the scalp. They pro- distribution, as well as age and sex incidence as posed that the pathological event unique to each HS. This condition is more convincingly associ- disease was follicular hyperkeratinization [19]. ated with an inflammatory process of the apo- All three diseases, HS, acne conglobata and crine duct. Of interest there have been descrip- dissecting folliculitis, represent chronic, recur- tions of some cases of Fox–Fordyce disease rent deep-seated folliculitis resulting in abscess- progressing to HS. es followed by sinus tract formation and - ring. In an actively inflamed lesion the sinus contains surrounded by neutrophils, gran- 4.6.2 Acne ulation and scar tissue (Fig. 4.7). In an end-stage lesion there is scarring with patchy inflamma- The pathogenesis of acne embraces increased tion, which may track down a healed sinus at the sebum production, follicular hyperkeratosis, site of a destroyed hair follicle. colonization with propionibacteria and inflam- The key histological features of all these con- matory changes. The sebaceous duct hyperkera- ditions are: tinization is mediated by the production of in- terleukin-1 alpha (IL1-A) and tumour necrosis 1. Poral occlusion of the pilosebaceous units factor alpha (TNF-A) by keratinocytes and T- within intertriginous skin sites, especially lymphocytes. The result is hyperproliferation of the axillary area and anogenital regions keratinocytes, reduced apoptosis and conse- 2. Secondary inflammation of apocrine quent hypergranulosis. As a result the sebaceous glands follicle becomes blocked with densely packed 3. Inflamed nodules and sterile , keratin and so evolves the . Early come- which are followed by sinus tracts, dones show a dilated hair follicle associated with fistulae and hypertrophic . infundibular hyperkeratosis. Later due to rup- ture an acute dermal inflammatory response ensues. This can be complicated by a foreign 4.6.4 Pilonidal Sinus body granulomatous reaction. In severe cases abscesses frequently present and cysts and si- In 1975 pilonidal sinus (PS) was reported to be- nuses form. Dermal scarring frequently results long to the category of follicular occlusion dis- in these cases. eases so creating the follicular tetrad [20]. His- topathological findings in PS show follicular 32 Alison Layton

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Fig. 4.8. Pilonidal sinus Fig. 4.10. Crohn’s disease with epithelioid granulomas

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 Fig. 4.9. Pilonidal sinus – CK17 was absent in type A authors have reported the co-morbidity of HS epithelium (original magnification= 100) and Crohn’s [23] (see Fig. 4.10).

hyperkeratosis of the infundibulum with plug- ging and dilatation of the follicle (Fig. 4.8). Su- 4.7 Conclusions perficially the sinus is often lined with stratified squamous epithelium but towards the deeper reaches the wall consists of granulation and scar W tissue. The early inflammatory event is perifol- The histological spectrum of HS is broad. The liculitis with neutrophils, lymphocytes and his- disease appears to be predominantly follicu- tiocytes leading to rupture of follicular epithe- lar and apocrine glands appear to be primarily lium. involved in only a minority of histological In a recent study using immunohistochemis- specimens. Although inflammation does not try with six antikeratin antibodies it has been appear to originate within the apocrine demonstrated that CK expression in PS is simi- glands, the exclusive finding of the disease lar to that in HS, suggesting that the epithelium within apocrine-gland-bearing skin indicates may be fragile, hyperproliferative and undiffer- Pathology of Hidradenitis Suppurativa Chapter 4 33

7. Attanoos RL, Appleton MAC, Douglas-Jones AG. an apocrine effect. This diversity of pathologi- The pathogenesis of hidradenitis suppurativa: a cal presentation may well explain the thera- closer look at apocrine and apoeccrine glands. Br J peutic challenge that this condition poses. Dermatol 1995; 133:254–258 8. Boer J, Weltevreden EF. Hidradenitis suppurativa or acne inversa: a clinicopathological study of early lesions. Br J Dermatol 1996; 135:721–725 Acknowledgements 9. Brunsting HA. Hidradenitis and other variants of acne. Arch Dermatol Syphilol 1952; 65:303–315 I would like to acknowledge the following peo- 10. Mortimer PS. Hidradenitis suppuritiva – diagnostic ple: criteria. In: Marks R, Plewig G (eds) Acne and Re- Professor I Kurokawa, Department of Der- lated Disorders. Martin Dunitz, London, 1989, pp 359–360 matology, Hyogo Prefectural Hospital, Japan, 11. Jemec GBE, Hansen U. Histology of hidradenitis for providing me with and permitting me to in- suppurativa. J Am Acad Dermatol 1996; 34:994– clude information and slides on the immuno- 999 histochemistry of HS and PS. 12. Mortimer PS, Lunniss PJ. Hidradenitis suppurativa. Dr Anne Gledhill, Department of Pathology, J R Soc Med 2000; 93:420–422 Harrogate and District Foundation Trust, UK 13. Weedon D. Skin Pathology. Churchill Livingstone, and Dr S Edwards Department of Pathology, Edinburgh, 1999, p 390 Leeds Teaching Hospital, UK, for providing his- 14. Fitzpatrick JE. Inflammatory reactions of the sweat unit. In: Farmer ER, Hood EF (eds) Pathology of tological sections of HS and related diseases. the Skin. Appleton and Lange, Norwalk, 1990, pp Dr Julian Barth, Department of Chemical 461–462 Pathology, Leeds Teaching Hospital, UK, for 15. Heller DS, Haefner HK, Hameed M. J Reprod Med providing valuable advice and information on 2002; 47(9):695–689 HS. 16. Norris JFB, Cunliffe WJ. A histological and im- Dr Anthony Yung, Department of Dermatol- munohistochemical study of early acne lesions. Br ogy, Leeds Teaching Hospital, UK J Dermatol 1988; 118:651–659 17. Layton AM, Morris C, Cunliffe WJ, Ingham E. Im- mmunohistochemical investigation inflammation in lesions of acne. Clin Exp Dermatol 1998; 7:191– References 197 18. Kurokawa I, Nishijima S, Kusumoto K. Immuno- 1. Velpeau A. Dictionnaire de Medicine, un Repertoire histochemical study of cytokeratins in hidradeni- General des Sciences Medicales Sous La Rapport tis suppurativa (acne inversa). J Int Med Res 2002; Theorique et Pratique. Aiselle, Bechet, 1839 30:131–136 2. Verneuil A. Etudes sur les tumours de la peau et 19. Pillsbury DM, Shelley WB, Kligman AM. Derma- quelques maladies des glandes sudoripares. Arch tology. Saunders, Philadelphia, 1956, p 481 Gen Med 1854; 4:447–468 20. Plewig G, Steger M. Acne inversa (alias acne triad, 3. Schiefferdecker B. Die Hautdrusen des Menschen, acne tetrad or hidradenitis suppurativa). In: Marks und der Saugetierre, ihre Histologische und rassena- R, Plewig G (eds) Acne and Related Disorders. Mar- natomische Bedeutung Sowie die Muscularis Sexu- tin Dunitz, London, 1988, pp 345–357 alis. Schweizerbart, Stuttgart, 1922 21. Kurokawa I, Nishijima S, Suzuki K. Cytokeratin 4. Brunsting HA. Hidradenitis suppurativa; abscess of expression in pilonidal sinus. Br J Dermatol 2002; apocrine sweat glands – a study of clinical and path- 146:409–413 ological features with a report of 22 cases and a re- 22. Attanoos RI, Appleton MA, Hughes LE. Granulo- view of the literature. Arch Dermatol Syphilol 1939; matous HS and cutaneous Crohn’s disease. Histo- 39:108–120 pathology 1993; 23:111–115 5. Shelly WB, Cahn MM. The pathogenesis of hidrad- 23. Church JM, Fazio VW, Lavery IC. The differen- enitis suppurativa in man. Arch Dermatol 1955; 72: tial diagnosis and comorbidity of HS and perianal 562–565 Crohn’s disease-a further support to this associa- 6. Yu CCW, Cook MG. Hidradenitis suppurativa: a dis- tion. Int J Colorectal Dis 1993; 8:117–119 ease of follicular epithelium, rather than apocrine glands. Br J Dermatol 1990; 122:763–769