Tale of Two Alopecias: Alopecia Areata and Central Centrifugal Cicatricial Alope

Sharlene Helene C. See, Timothy L. Tan, Oyinade Aderibigbe, Pedram Yazdan,∗

1Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; 2Consolidated Pathology Consultants, Libertyville, IL 60048, USA; 3Department of Dermatology, Division of Dermatopathology, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.

Abstract

Keywords: alopecia areata, central centrifugal cicatricial alopecia, non-scarring alopecia, scarring alopecia,peptidylarginine deiminase type III gene∗Corresponding author: Dr. Pedram Yazdan, Department of Dermatology,Northwestern University, Chicago, IL 60611, USA. E-mail: pyazdan@nm.org Conflicts of interest: The authors reported no conflicts of interest.

Introduction

Alopecias are broadly divided into non-scarring and scarring variants. Clinically, non-scarring alopecias have preserved follicular ostia, typically lack signs of inflammatory change, and hair regrowth is possible. Histologically, non-scarring alopecias lack evidence of hair follicle destruction and fibroplasia.Conversely,scarring alopecias show loss of follicular ostia, with follicles being replaced by fibrotic tracts and hyalinized collagen, resulting in permanent hair loss.

Alopecia areata (AA) is an autoimmune non-scarring alopecia that classically presents with well-defined smooth patches of hair loss.AA has a lifetime incidence of 2%,has no racial or sexual predilection, and usually occurs in patients aged 15–40years.1The pathogenesis is thought to involve a breakdown of the immune privilege of the hair follicles.Stress has also been implicated in the pathogenesis of AA,with substance P and nerve growth factor acting as key mediators. Histologically, the classic diagnostic pathologic feature of the acute phase of AA is peribulbar lymphocytic inflammation likened to a “swarm of bees” affecting the anagen follicles or follicles in early catagen. Other histological findings of AA include markedly miniaturized hair follicles and the possible presence of pigment casts, eosinophils, and melanin in fibrous tracts.

Central centrifugal cicatricial alopecia (CCCA) is a progressive scarring alopecia that most often occurs in individuals of African heritage.CCCA typically begins on the vertex and/or crown of the scalp and extends outward in a radial fashion.Examination of CCCA lesions reveals a loss of hair follicle openings,and some patients may have symptoms of pruritus, burning, and/or scalp tenderness.The cause of CCCA is still unknown and is most likely multifactorial, with haircare practices and genetic predisposition hypothesized to play key roles. Histopathologic examination of CCCA lesions reveals destruction of hair follicles,perifollicular fibroplasia,eccentric thinning of the outer hair follicle epithelium, and premature desquamation of the inner hair follicle root sheath at the level of the lower isthmus.

Scarring and non-scarring alopecias have rarely been described to occur concurrently in the same patient.Moreover, concomitant AA and CCCA has never been reported. Herein, we present a unique case of AA occurring simultaneously with CCCA.To our knowledge,this is the first case report of these two specific types of alopecia occurring together.

Case report

The patient was a 35-year-old African-American woman presenting with new alopecic patches on the frontal scalp and vertex scalp over one month.The alopecic area on her vertex scalp was associated with pruritus,tenderness,and a tingling sensation. She typically styled her hair in tight braids around the crown and noted that her hair loss seemed to worsen with job-related stress. She had no significant past medical history, including autoimmune diseases, but reported a family history of hair loss in her mother and grandmother.Physical examination revealed a well-demarcated patch of alopecia on the frontal scalp(Fig.1A);on dermoscopic evaluation,there were preserved follicular ostia, miniaturized hair follicles, yellow dots,and shortened exclamation mark hairs. Examination of her vertex scalp showed an irregular area of alopecia with decreased hair density (Fig. 2A); dermoscopy was suspicious for loss of follicular ostia, but there was no erythema or perifollicular scaling. Given the clinical suspicion of both scarring and non-scarring alopecias,the areas of alopecia were biopsied. Biopsy of the frontal scalp revealed a markedly increased proportion of telogen,catagen, and miniaturized hair follicles; there was also dense lymphocytic infiltrate surrounding the hair bulbs without fibroplasia or interface inflammation, consistent with AA (Fig. 1B and 1C). Biopsy of the vertex scalp revealed a decreased number of hair follicles,variably sized follicles,perifollicular fibroplasia,eccentric atrophy of the outer hair follicle epithelium,premature desquamation of the inner root sheath at the level of the lower isthmus,and fused hair follicles consistent with CCCA(Fig.2B and 2C);peribulbar lymphocytic inflammation typical of AA was not identified in this biopsy (Fig. 2D).

The diagnosis of AA combined CCCA was made based on the clinical and histopathological results.The patient was treated with intralesional corticosteroid injections every 4weeks,topical fluocinolone oil three to four times per week,minoxidil 5%solution once a day,and 100mg of oral doxycycline twice daily. She also stopped using tight braids for some time. The tingling sensation and pruritus on her vertex scalp resolved after the corticosteroid injections and topical corticosteroids.Her AA on the frontal scalp showed significant improvement over a course of 5months(Fig.1D).Within a 1.5-year period, the AA occasionally recurred but improved with intralesional corticosteroids. However,the CCCA on her vertex showed minimal to no improvement, and recently worsened with the use of sewed-in French braids.The patient gave her agreement for case publication.

Discussion

Our patient presented with typical histologic findings of CCCA and AA on the vertex and frontal scalp,respectively.

The clinical differential diagnoses for the lesion on our patient’s vertex included CCCA,lichen planopilaris(LPP),androgenetic alopecia, and telogen effluvium. However,the loss of follicular ostia suggested a scarring alopecia,ruling out non-scarring alopecias such as androgenetic alopecia and telogen effluvium.Furthermore,there was no perifollicular erythema and scaling characteristic of LPP,and histologic sections did not reveal lichenoid infiltrates around the infundibulum, vacuolar interface changes, or perifollicular mucin.

The differential diagnoses for the relatively well-circumscribed smooth patch of alopecia on our patient’s frontal scalp included AA, triangular temporal alopecia, traction alopecia, trichotillomania, syphilitic alopecia, and lupus erythematosus. Preservation of the follicular ostia in this area made scarring alopecias such as syphilitic alopecia and lupus erythematosus less likely. Furthermore, the negative treponema antibody test and lack of pigmentation changes made discoid lupus erythematosus unlikely.Triangular temporal alopecia usually presents during childhood and histology would show a normal number of vellus hair follicles. Trichotillomania would show trichomalacia and pigment casts,while traction alopecia would have presented with fibrotic fibrous tracts and mild to absent inflammation.

There have been very few case reports of scarring and non-scarring alopecias occurring together. Fukuyama et al.2reported coexisting AA and LPP,with intralesional steroids resulting in complete hair regrowth in the AA regions but only suppression of further hair loss in the area of LPP.The coexistence of AA and frontal fibrosing alopecia (FFA) has also been described. McSweeney et al.3reported a 78-year-old woman with a 6-year history of FFA who subsequently developed AA, and theorized that the likely underlying mechanism of the alopecic dimorphism was the coexistence of a permissive genetic background and exogenous stressors or substrate exposure. Lin et al.4reported two patients with AA who also subsequently developed FFA;they proposed several possible reasons for the cooccurrence, including immune dysregulation associated with hormonal changes during puberty and menopause,stress and neuropeptides, and melanocyte-derived autoantigens.

It appears that the purported underlying mechanism of AA concurrent with either LPP or FFA is the loss of immune privilege in the hair follicle.It has been postulated that LPP and FFA mirror the autoimmune process in AA.One noted difference between LLP or FFA and AA is that the CD8+T-cell-mediated inflammation in LPP or FFA occurs at the bulge, which contains crucial stem cells leading to permanent hair loss, whereas inflammation in AA occurs at the bulb.4

Cicatricial alopecias are hypothesized to occur through loss of the immune privilege in the bulge area.Deletion of CD200 in the outer root sheath of murine hair follicles may be responsible for eliciting the danger signal responsible for the inflammatory process. Dysregulation of p53,expression of Fas,and decreased expression of Bcl-2 may also play crucial roles.5In addition, patients with CCCA have upregulation of fibroproliferative genes such as platelet-derived growth factor, collagen gene I and III,and matrix metalloproteinase genes 1, 2, and 7.5CCCA can also be inherited in an autosomal dominant fashion,with partial penetrance, and a strong modifying effect of haircare practices and gender.6

Subash et al.5attempted to combine all these mechanisms together and proposed a novel pathogenetic mechanism for CCCA in which a genetic predisposition primes the scalp hair follicles to be susceptible to unknown external factors that then trigger an autoimmune lymphocytic response.This in turn leads to increased transforming growth factor-β,activation of fibroblasts,and endothelialto-mesenchymal transition, resulting in fibrosis.5

Figure 1. Alopecia areata component.(A)Physical examination shows a well-demarcated patch of alopecia on the frontal scalp.(B)Biopsy of this area reveals peribulbar lymphocytic inflammation, markedly increased proportions of telogen/catagen and miniaturized hairs, preserved sebaceous glands, and a lack of dermal fibroplasia or destruction of hair follicles (H&E, × 20). (C) High-powered view shows prominent peribulbar lymphocytic inflammation and pigment incontinence(H&E,×400).(D)Complete regrowth in the frontal scalp area occurred during a 1.5-year period. H&E: hematoxylin and eosin.

Figure 2. Central centrifugal cicatricial alopecia component.(A)An irregular area of alopecia with decreased hair density.(B)Biopsy shows a decreased number of variably sized follicles,premature desquamation of the inner root sheath at the level of the lower isthmus,eccentric atrophy of the outer hair follicle epithelium,and fusion of follicles(H&E,×20).(C)High-powered view shows premature desquamation of the inner root sheath,fused follicles,and perifollicular fibroplasia(H&E,×200).(D)Deeper sections reveal the absence of peribulbar lymphocytic inflammation(H&E, × 20). H&E: hematoxylin and eosin.

Most recently, peptidylarginine deiminase type III gene(PADI3) missense mutation has been implicated in the pathogenesis of CCCA.PADI3 is a member of the peptidyl arginine deiminase family of enzymes, is responsible for modifying proteins critical for normal hair shaft formation and shaping, and may also play a role in interfollicular epidermal differentiation. Malki et al.7confirmed that reduced PADI3expressionmayleadtoa deleteriouseffectin hair shaft formation and follicle development in CCCA.Interestingly,Oka et al.8identified a novel AA susceptibility variant (rs142986308,pArg587Trp)in the CCHR1 gene.Alopecic mice and patients with AA carrying the risk allele show differential expression of hair-related genes,including PADI3. The genetic basis of AA has been supported by studies showing concordance rates of 42%–55% in monozygotic twins.9Thus,it is possible that genetic overlap may play an important role in the co-occurrence of CCCA and AA. This hypothesis warrants investigation in future larger studies that perform comprehensive genetic testing of patients with CCCA and AA.

The treatment strategies for AA and CCCA may overlap.Both AA and CCA can be treated with intralesional and topical corticosteroids, topical minoxidil, and oral cyclosporine. However, the other treatment options vary greatly, and the prognosis of each condition is different.Hair regrowth is achievable for AA, Janus kinase inhibitors are emerging as a promising therapy. Other treatment options for moderate to severe AA include diphenylcyclopropenone, laser, and squaric acid dibutylester. In certain cases, systemic therapies including systemic corticosteroids, methotrexate, cyclosporine, and azathioprine have also been used.The treatment of CCCA is aimed at prevention of further permanent hair loss including halting the scarring process and removal of potentially damaging haircare practices. Topical and intralesional corticosteroids are usually the first line of treatment. Anti-inflammatory treatments, including oral tetracyclines and antimalarials,have been used for CCCA with variable success. Other treatments include topical minoxidil, topical calcineurin inhibitors, thalidomide,mycophenolate mofetil, vitamins, and cyclosporine. In our patient, the regimen of intralesional corticosteroids,topical corticosteroids, topical minoxidil, and oral doxycycline resulted in improvement of the AA area, but minimal to no improvement of the CCCA area.

A possible reason why there have been very few case reports of AA occurring together with scarring alopecias is that similar lesions may have been misdiagnosed as AA.However,it is crucial to distinguish between scarring and non-scarring alopecias, as the treatment strategies and prognoses are considerably different. The importance of recognizing scarring alopecias such as CCCA cannot be overemphasized, as earlier diagnosis may halt disease progression,and therefore,lead to an improved quality of life.