Histologic progression of acne inversa/hidradenitis suppurativa: Implications for future investigations and therapeutic intervention

Abstract

Since first recognized in 1839, the pathogenesis of acne inversa (AI) has undergone repeated revisions. Although there is agreement that AI involves occlusion of hair follicles with subsequent inflammation and the formation of tracts, the histologic progression of this disease still requires refinement. The objective of this study was to examine the histologic progression of AI based on the examination of a large cohort of punch biopsies and excisional samples that were examined first by hematoxylin and eosin staining. The most informative of these samples were step-sectioned and stained by immunohistochemistry for epithelial and inflammatory markers. Based on this examination, the following observations were made: 1) AI arises from the epithelium of the infundibulum of terminal and vellus hairs; 2) These form cysts and epithelial tendrils that extend into soft tissue; 3) Immunohistochemical staining demonstrates the epithelium of AI is disordered with infundibular and isthmic differentiation and de novo expression of stem cell markers; 4) The inflammatory response in AI is heterogeneous and largely due to cyst rupture. The conclusions of this investigation were that AI is an epithelial-driven disease caused by infiltrative, cyst forming tendrils and most of the inflammation is due to cyst rupture and release of cornified debris and bacteria. Cyst rupture often occurs below the depths of punch biopsy samples indicating their use for analysis may give an incomplete picture of the disease. Finally, our data suggest that unless therapies inhibit tendril development, it is unlikely they will cause prolonged treatment-induced remission in AI.

Keywords: Hidradenitis suppurativa; diseases; hair follicle; inflammatory skin; pathogenesis.

FIGURE 1

An excisional biopsy from a patient with AI. All infundibula in this section demonstrate early to progressive lesions defined by hyperplasia of infundibular outer sheath epithelium (black asterisks define terminal follicles, red asterisks define vellus follicles). There are also small tendrils extending from the hyperplastic epithelium (arrows). H&E stain, magnification 1.4x

FIGURE 2

Tendrils are a defining feature of AI. They develop early in the disease before rupture of the infundibular lumen. (A) Early tendrils (arrowheads) from a follicular infundibulum. (B) More extensive and deeper extension of tendrils (arrowheads) with the formation of a new cyst (asterisk). (B). Higher power of tendrils defining their growth does not require substantive inflammation to progress. H&E stain, magnification A = 3.6, B = 1.6x, B1 = 16.5x

FIGURE 3

Severely inflamed Hurley stage III. There are many continuous and interconnecting tendrils/cysts extending into deeper soft tissues (asterisks), best defined by IHC staining for K5 in (B). The presence of tendrils extending into deep soft tissues indicts that they can develop in spite of intense inflammation. (A) = H&E stain; (B) = immunostaining for K5, fast red chromogen, haematoxylin counter stain, magnification both images, 0.7x

FIGURE 4

Proposed histologic progression of AI (not to scale). (A) Lesions start with hyperplasia of the infundibular outer root sheath. (B) From the infundibulum, branching tendrils extend in adjacent soft tissues. (C) As lesions evolve, cornified cysts form and from these cysts, new tendrils form that can have cornified lumens. (D) Although mild inflammation can occur at all stages of development, substantive inflammation is associated with a breach in the cyst or lumen wall and extrusion of luminal cornified debris and bacteria. (E) As inflammation intensifies cysts can be destroyed and necrotic tendrils result in the formation of non/minimally epithelial‐lined tunnels