Aims. Background. Definition

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1 REVIEW ARTICLE BJD British Journal of Dermatology How not to get scar(r)ed: pointers to the correct diagnosis in patients with suspected primary cicatricial alopecia M.J. Harries,* R.M. Trueb,à A. Tosti, A.G. Messenger, I. Chaudhry,** D.A. Whiting, C.E.M. Griffiths* and R. Paus* *Dermatological Sciences, The University of Manchester, Salford Royal Hospital, Manchester M6 8HD, U.K. Department of Dermatology, University of Lübeck, D Lübeck, Germany àdepartment of Dermatology, University Hospital of Zurich, Zurich, Switzerland Department of Dermatology, University of Bologna, Bologna, Italy Department of Dermatology, University of Sheffield, Hallamshire Hospital, Sheffield, U.K. **Department of Histopathology, Manchester Royal Infirmary, Manchester, U.K. Baylor Hair Research and Treatment Centre, Dallas, TX, U.S.A. ààdepartment of Dermatology, University of Melbourne, Melbourne, Australia Summary R. Sinclair,àà Correspondence Matthew Harries. Accepted for publication 21 October 2008 Key words alopecia, diagnosis, review Conflicts of interest None declared. DOI /j x Primary cicatricial alopecias (PCAs) are a rare, but important, group of disorders that cause irreversible damage to hair follicles resulting in scarring and permanent hair loss. They may also signify an underlying systemic disease. Thus, it is of paramount importance that clinicians who manage patients with hair loss are able to diagnose these disorders accurately. Unfortunately, PCAs are notoriously difficult conditions to diagnose and treat. The aim of this review is to present a rational and pragmatic guide to help clinicians in the professional assessment, investigation and diagnosis of patients with PCA. Illustrating typical clinical and histopathological presentations of key PCA entities we show how dermatoscopy can be profitably used for clinical diagnosis. Further, we advocate the search for loss of follicular ostia as a clinical hallmark of PCA, and suggest pragmatic strategies that allow rapid formulation of a working diagnosis. Scalp hair is an important component of body self-image in humans. Hair styles are commonly used to express individuality and increase sexual attractiveness. Therefore, it is no surprise that hair loss can have a marked impact on a person s psychological status, quality of life and social interaction, 1 3 not just through concern about the impact it may have on their appearance, but also whether it may signify a serious underlying disease. While this is true for essentially all forms of cosmetically disturbing hair loss, in cicatricial alopecias the situation is aggravated by the usually irreversible and often progressive nature of the condition. Cicatricial alopecias are a rare, but important, group of disorders that cause irreversible damage to hair follicles resulting in scarring and permanent hair loss. 3 8 In some situations they may also be associated with an underlying systemic disease. 7 For these reasons it is: (i) a priority to exclude or confirm the presence of a cicatricial alopecia, and (ii) of paramount importance that every clinician who manages patients with hair loss is able to diagnose these disorders accurately. Unfortunately, as this review will highlight, the latter is often more difficult than it sounds. Aims The aim of this review is to present a rational and pragmatic guide which allows clinicians to assess, investigate and ultimately diagnose patients with cicatricial alopecia. This paper is the second in a series of reviews that attempt to offer a comprehensive overview of cicatricial alopecias, focusing on primary cicatricial alopecia (PCA). The current review of the diagnosis of PCA complements our published, evidence-based account of treatment options in PCA. 4 Background Definition Cicatricial alopecia may be diagnosed on both clinical and histopathological grounds. In the clinical setting, the normally visible follicular ostia are lost, often, but not invariably, within an area of visible scarring. In many cases, this is concomitant with at least some degree of epidermal atrophy and other textural skin architecture changes. On histological examination 482

2 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. 483 Fig 1. Cardinal signs of primary cicatricial alopecia (PCA). (a) Loss of visible follicular ostia. (b) Loss of visible follicular ostia (dermatoscopy view). (c) Histological hallmark of PCA showing follicle loss with replacement by fibrous tissue (haematoxylin and eosin; original manification 20). the hair follicles are destroyed and replaced with scar-like fibrous tissue (Fig. 1). 7,9 14 Primary vs. secondary cicatricial alopecia In PCA the hair follicle itself is the main target of the disease. In contrast, secondary cicatricial alopecias (e.g. skin cancer, thermal burns, sarcoidosis, or a consequence of ionizing radiotherapy) develop follicular damage coincidently as part of a more generalized destructive process within the skin, which ultimately destroys the hair follicle s stem cell-based capacity for repeated regeneration. 2,5,6,10 This review will focus on PCA. Epidemiology Data from various specialist hair centres in North America suggest that PCAs are relatively uncommon, even considering the highly selected cohort of patients studied At one centre the frequency of cicatricial alopecias seen was 3Æ2% between 1997 and 2001, while another reported a cicatricial alopecia frequency of 7Æ3% over a 10-year period. 14,15 Although the exact prevalence within the general population remains unknown, it is likely to be substantially lower than the figures reported above. Pathogenesis The exact pathogenesis of any of the PCAs is currently unknown. However, all forms of PCA probably result from irreversible damage to the epithelial hair follicle stem cells that reside in a protected area of the outer root sheath called the bulge. 17,18 The bulge is located in the upper third of the hair follicle at the level of the insertion of the arrector pili muscle (Fig. 2a,b). Morphologically, in some patients, this often Fig 2. (a) Hair follicle anatomy (from Whiting, 106 courtesy of Canfield Publishing). (b) Hair follicle anatomy showing the bulge region (haematoxylin and eosin; original magnification 20). (c) The follicular trochanter 19 (arrows) may be a useful morphological marker of the bulge region in humans (haematoxylin and eosin; original magnification 100).

3 484 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. markers remain to be identified for any of the currently recognized PCA entities. 6,23 4 The PCA literature is often confusing due to inconsistent use of terminology and poor disease definition. 7,21 These problems are compounded by our poor knowledge of the natural history of the different PCA diseases, the lack of good quality evidence for treatment 4 and our current inability to monitor disease progression objectively and effectively over time. Fig 3. The pattern of inflammatory infiltrate typically seen in permanent and reversible alopecias. Red dots = inflammatory infiltrate. (Adapted from Cotsarelis and Millar 107 ). difficult to identify bulge can be recognized by searching for a peculiar protrusion of the outer root sheath, for which the term follicular trochanter has been suggested (Fig. 2c). 19 It is thought that inflammation in the area of the bulge somehow destroys the epithelial hair follicle stem cells located here and, in so doing, removes the follicle s potential for regeneration. 5,6,20,21 It is interesting to compare the pattern of inflammation in PCA with that of the prototypical nonscarring inflammatory hair disorder, alopecia areata. 2,21 Despite the often marked peribulbar inflammation seen in alopecia areata, the follicles are not permanently destroyed, presumably because the bulge region is unaffected by the disease process (Fig. 3). The fact that mutant mice with a targeted deletion of keratin 15-expressing hair follicle epithelial progenitor cells show a striking loss of hair follicles, yet fail to develop signs of scarring, 20 suggests that the loss of epithelial stem cells is not the only element of PCA pathogenesis. Classification The North American Hair Research Society (NAHRS) has attempted to address some of these difficult issues by organizing a workshop on PCA. By consensus opinion, a working classification was produced that is based primarily on the predominant inflammatory infiltrate found on scalp biopsy. Once a patient had been classified into a specific histological subgroup, the disease could be identified based on the salient clinical features (Table 1). 25 Recommendations for both clinical and histological minimum datasets were also proposed so as to improve diagnosis and management, as well as facilitate research collaboration. Clinical assessment When approaching a patient with suspected scarring hair loss, it is prudent to follow a few simple rules, as follows. 1 Take a careful history. Particularly concentrate on the disease onset and progression, local and systemic symptoms, and other skin, nail or mucous membrane changes. A history of lupus erythematosus (LE), other autoimmune diseases or lichen planus (LP) should be sought and previous hair-care Problems with diagnosis of primary cicatricial alopecias Primary cicatricial alopecias are notoriously difficult to diagnose. While the observant clinician will soon notice clinical signs that point to the presence of some form of cicatricial alopecia, accurate classification is less straightforward, or (rarely) cannot be made at all. This difficulty results from the following factors: 1 The clinical and histological features may change over time as the disease evolves. At the time of examination the PCA may have already progressed to an advanced stage of hair follicle and skin degeneration, thereby eliminating any of the key diagnostic indicators. PCAs appear to follow a final common pathway in end-stage disease, characterized by complete follicular destruction, replacement with fibrous tissue and absence of an inflammatory infiltrate. At this stage specific disease classification may be impossible Overlapping clinical and pathological features make distinguishing one condition from another difficult, and at times impossible. 13,14 3 No single clinical or pathological feature is diagnostic for a particular form of PCA. 7 Conclusive and specific molecular Table 1 The North American Hair Research Society classification of primary cicatricial alopecias 25 Inflammatory infiltrate Lymphocytic Neutrophilic Mixed Nonspecific (end-stage) Diagnosis Chronic cutaneous lupus erythematosus Lichen planopilaris Classic lichen planopilaris Frontal fibrosing alopecia Graham Little syndrome Classic pseudopelade of Brocq Central centrifugal cicatricial alopecia Alopecia mucinosa Keratosis follicularis spinulosa decalvans Folliculitis decalvans Dissecting cellulitis folliculitis (perifolliculitis abscedens et suffodiens) Folliculitis (acne) keloidalis Folliculitis (acne) necrotica Erosive pustular dermatosis

4 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. 485 Table 2 Dermatoscopy features of primary cicatricial alopecias Diagnosis Lichen planopilaris Chronic cutaneous lupus erythematosus Folliculitis decalvans Dermatoscopy features Absent follicular openings; follicular plugging; hair casts; peripilar white dots (dark-skinned patients); interfollicular simple red loops; arborizing red lines; honeycomb pigment; patchy deep pigmentation Absent follicular openings; red dot pattern of follicular openings (early disease); follicular plugging; hyperkeratotic perifollicular scaling; arborizing red lines Scalp oedema; crusts; peripilar casts; coiled dilated capillaries; tufted hairs; twisted red loops practices (e.g. use of hot combs, excessive traction) documented. 2 2 Carefully examine the scalp skin. Close inspection of the area of hair loss is mandatory, aided by a magnifying lens or dermatoscope, to appreciate the disappearance of the normal follicular ostia and identify any associated changes in skin texture (Table 2) As dermatoscopy offers very fast and highly instructive clues to PCA diagnosis, it is strongly recommended for the clinical examination of every case of PCA. 28 Irregularly spaced hair shafts and hair tufting ( doll s hair ) are additional clues to a scarring process. 2 Erythema, scaling and perifollicular hyperkeratosis should be recorded along with any signs of atrophy, dyspigmentation, pustules or crusting. The pattern of hair loss (e.g. central, multifocal, frontal) and the extent of scalp involvement should be estimated and monitored. 25 TIP Patient symptoms (e.g. pruritus, scalp tenderness) can often be used to guide the clinician to active areas of disease that may otherwise have been overlooked and often represent a particularly fruitful area to biopsy. 7 For example, scalp itching is a typical early sign of lichen planopilaris (LPP) and may be associated with minimal signs of scarring at disease onset. 3 Look for tufted hairs. These are multiple hairs emerging from a single follicular ostium. Hair tufting in PCA probably results from upper dermal inflammation destroying the distal follicle. As the skin heals the hairs are then pulled together to emerge through a common follicular ostium. 29,30 Hair tufting is commonly seen in folliculitis decalvans (FD) tufted folliculitis but is not pathognomonic of this disorder and may be seen in other PCA entities. 29 CAUTION A small number of hairs emerging through the same follicular ostium is often a normal finding Perform a hair pull test. Active hair loss (i.e. disease activity) can be assessed reliably, quickly and easily on different areas of the scalp during clinical assessment. Grip approximately 20 hairs near to the scalp, gently pulling upwards and away from the skin. The extraction of anagen hairs with thickened root sheaths strongly suggests cicatricial alopecia, even if Fig 4. Positive pull test revealing anagen bulbs with attached inner and outer root sheaths. the pull test does not reveal increased hair loss (Fig. 4). Therefore, even though only a few hairs may be extracted, the pull test is always regarded as pathological if anagen hairs are present. 5 Examine the rest of the skin. Particularly look for evidence of LE (e.g. face, ear lobes) or LP (e.g. oral cavity, genitalia, nails) in other anatomical regions besides the scalp. 6 Photograph the scalp. Photographic documentation allows objective assessment of disease extent and progression with time. 25 In practice, however, this may be difficult as patches of alopecia are often irregular and look very different, depending on how the remaining hair is parted. It is best to choose a target area and standardize the image (i.e. light, angle, distance). 7 Take samples for microscopy, culture and sensitivity (bacterial and fungal) if crusting, pustules, bogginess or scale are present. Fungal infections may induce a secondary cicatricial alopecia that may mimic various recognized PCA entities Remember, pustules can also be seen in normal scalps, fungal infections, LPP and discoid LE, 37,38 and are not pathognomonic for FD. 8 Arrange a skin biopsy of the scalp. 9 Follow the flowcharts (Figs 5, 6) to reach a provisional diagnosis. 10 Consider referral to a hair loss specialist for advice and or incorporation into an ongoing research study clinical trial. The scalp biopsy Scalp biopsy is a vital component of the assessment in PCA as it will not only determine the predominant inflammatory infiltrate used for disease classification (Table 1), 25 but can also be used to confirm scarring (if doubt exists) and helps to identify secondary causes of cicatricial alopecia. Unfortunately, scalp biopsies are often inadequate so that even the most expert pathologist cannot possibly reach a

5 486 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. Fig 5. Flowchart 1. Clinical probability flowchart for primary cicatricial alopecia (PCA). LPP, lichen planopilaris; CCLE, chronic cutaneous lupus erythematosus; FFA, frontal fibrosing alopecia; AM, alopecia mucinosa; KFSD, keratosis follicularis spinulosa decalvans; PB, pseudopelade of Brocq; CCCA, central centrifugal cicatricial alopecia; DCS, dissecting cellulitis of the scalp; FD, folliculitis decalvans; AKN, acne keloidalis nuchae; ANV, acne necrotica varioliformis; EPDS, erosive pustular dermatosis of the scalp. diagnosis. Common errors include too small or superficial samples, crush artefact, cross-cutting of follicles or poor selection of biopsy site. Two 4 6-mm punch biopsies should be taken from active lesions, usually at the edge of the bald patch that is clinically affected by the inflammatory process, yet still contains a reasonable number of follicles. To stand any chance of diagnosing PCA accurately, the type and pattern of inflammation affecting the follicle before it has been completely destroyed need to be seen. Do not biopsy a completely bald, atrophic end-stage area of alopecia as the pathologist will see only nonspecific scarring. The punch biopsy instrument should be orientated parallel to the direction of hair growth so as to avoid the blade cutting across the follicles within the specimen (Fig. 7 correct technique). If follicles are cross-cut it can significantly reduce the number of diagnostic follicles available to the pathologist and thereby sharply reduces the information gained from the procedure. 11 Histopathology assessment For optimal results, one biopsy should be processed for horizontal sectioning and the other for vertical sectioning. 11,39 42 The biopsy destined for vertical sectioning is then bisected, enabling one half to be formalin fixed and processed for paraffin embedding and routine histology (haematoxylin and eosin), and the other to be snap-frozen and processed for immunofluorescence studies. The latter technique is primarily advised when autoimmune disorders (e.g. LE, vesiculobullous diseases) are suspected or when the biopsy material is to be used for research purposes. Additional histochemical stains, besides haematoxylin and eosin, for elastin (Verhoeff van Gieson; VVG), mucin (alcian blue), mast cells (toluidine blue; Giemsa) and periodic acid Schiff may improve diagnostic yield (see below). 43 To optimize histopathological reporting the NAHRS workshop on PCA devised a pathology minimum dataset to be completed for every case of suspected cicatricial alopecia. 25 This dataset prompts the recognition and reporting of key features for diagnosis of PCA, including hair follicle density and structure, adnexal involvement, epithelial changes, type and distribution of inflammatory infiltrate, degree and location of fibrosis, and interstitial changes. Immunofluorescence may improve diagnostic yield in certain situations, particularly if standard histopathology is inconclusive and cutaneous LE or a bullous disorder are suspected on clinical grounds. 44 However, caution is required as false-positive results may be seen in chronically sun-damaged skin. 45 Elastin stains (VVG) may improve diagnostic yield, particularly in end-stage disease that no longer displays an identifiable inflammatory infiltrate. VVG staining patterns for each PCA entity are summarized in Table 3, which also summarizes salient histopathological features of the major PCA entities. Steps to diagnosis Step 1. Is this a scarring alopecia? Having assessed the patient, the first step is to identify if the hair loss is the result of scarring. This is not always easy. We

6 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. 487 Fig 6. Flowchart 2. Histopathology diagnostic flowchart for primary cicatricial alopecia (PCA). LPP, lichen planopilaris; CCLE, chronic cutaneous lupus erythematosus; FFA, frontal fibrosing alopecia; AM, alopecia mucinosa; KFSD, keratosis follicularis spinulosa decalvans; PB, pseudopelade of Brocq; CCCA, central centrifugal cicatricial alopecia; DCS, dissecting cellulitis of the scalp; FD, folliculitis decalvans; AKN, acne keloidalis nuchae; ANV, acne necrotica varioliformis; EPD EPDS, erosive pustular dermatosis of the scalp; BMZ, basement membrane zone; IMF, immunofluorescence; PAS, periodic acid Schiff; ORS, outer root sheath. *Elastin staining pattern not known for AM and KFSD. recommend good lighting along with optical magnification from a hand-lens, plus use of a dermatoscope. 27,28 Thus armed, search for loss of visible follicular ostia and epidermal atrophy. Proceed to step 2 when these clinical indicators of PCA are positive, or if scarring cannot be definitely excluded, especially when other signs are present that can be associated with PCA (e.g. skin sclerosis, pustules, crust). If the hair loss is deemed to be nonscarring in nature, do not proceed, but follow available guides on how to assess and manage nonscarring hair loss. 5,9,46

7 488 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. Fig 7. The punch biopsy direction (large arrow) must run parallel to the remaining visible hair shafts to avoid cross-cutting the follicles. The biopsy must also be deep enough to sample the whole terminal hair follicle (i.e. extend into the subcutaneous fat). Step 2. What is your provisional clinical diagnosis? Although the usefulness of clinical inspection in PCA can sometimes be limited, a provisional differential diagnosis can usually be formulated based on the clinical features expressed. Use the clinical probability flowchart (flowchart 1, Fig. 5), the disease summaries and diagnostic tips below to narrow the clinical diagnosis. Additional clues can be gained from photographs of each condition (Figs 8 19) and the additional clinical details listed in Table 3. TIP Answer the following questions: 1 What is the patient s ethnic origin? Some conditions appear disproportionately over-represented in certain racial groups. 47 Central centrifugal cicatricial alopecia (CCCA), 48,49 acne keloidalis nuchae (AKN) 50 and dissecting cellulitis of the scalp (DCS; perifolliculitis capitis abscedens et suffodiens) 51 are almost exclusively found in those of African descent. However, exceptions do occur, but rarely. 49, What is the patient s age? Erosive pustular dermatosis (EPD) is reported primarily in elderly patients Frontal fibrosing alopecia (FFA) is seen predominantly in postmenopausal women, while keratosis follicularis spinulosa decalvans (KFSD) has an onset in late childhood or adolescence What is the scalp distribution? Certain conditions have characteristic locations within the scalp. Lesions of AKN are typically located on the occipital scalp, whereas FFA displays a distinctive band-like recession of the frontal hairline. 7,14,50,59,60,68 4 Are other nonscalp regions involved? Eyebrow alopecia is commonly seen in FFA and KFSD. 59,60,66,67 Chronic cutaneous lupus erythematosus (CCLE) is rarely solely limited to the scalp, with reports suggesting that coexisting lesions occur at other body sites in 80 90% of cases. 37,69 Diagnostic confidence may be greatly increased when typical nonscalp lesions of LP coexist with LPP. Some papers report extrascalp LP in up to 50% patients with LPP at some point during the course of the disease. 38 However, in practice these figures appear too high. For example, of 167 patients with biopsy-proven classic LPP seen at one European centre, two had nail LP, seven cutaneous LP and 36 oral LP (A. Tosti, unpublished data). 5 What is the most likely diagnosis? Contrary to previously published reports 15 it is the experience of the coauthors of this review that LPP and its variants are by far the most commonly encountered forms of PCA seen in general dermatological practice. Unfortunately no reliable data on the incidence and prevalence of defined PCA entities are as yet available. Therefore, LPP represents a sensible starting point when formulating your diagnosis. Use of the enclosed simplified flowchart will help reach a provisional diagnosis (Flowchart 1, Fig. 5). If you still experience difficulties in reaching a provisional diagnosis, scan Table 3 and the following summaries of the major forms of PCA for additional clues. Lichen planopilaris and variants These are illustrated in Figures 8 and 9. Classical LPP is characterized by multifocal patches of permanent alopecia distributed over the central scalp. Lesional skin displays perifollicular erythema and follicular hyperkeratosis, usually within the hairbearing rim of inflammation that surrounds the expanding edge of hair loss. 7 Other variants of LPP include FFA and Graham Little syndrome. Additionally, the recently described entity fibrosing alopecia in a pattern distribution (FAPD) may also be a variant of LPP. 25,70 In FFA, a band-like symmetrical recession of the frontal hairline, with associated scarring, is seen. Perifollicular erythema and follicular hyperkeratosis within the hair-bearing margin indicate ongoing disease activity. The zone of hair loss is typically much paler than that of the sun-exposed facial skin and this can be used to indicate the position of the original hairline (Fig. 9a). 59,60 Associated alopecia of the eyebrows is common 60 and nonscarring hair loss of the axillae and limbs may also be seen. 61,62,64 The diagnosis of Graham Little syndrome is suggested by the clinical triad of patchy, progressive scarring alopecia, nonscarring alopecia of axillary and pubic hair and the presence of widespread horny follicular (keratosis pilarislike) papules on the trunk and limbs (Fig. 9b,c) FAPD is characterized by scarring hair loss within areas of androgenetic alopecia (Fig. 9d). Although it is unknown whether FAPD is a variant of LPP, it appears to represent a lichenoid tissue reaction directed against miniaturized scalp hair. 70 Chronic cutaneous lupus erythematosus Cicatricial alopecia is a common feature in CCLE (Fig. 10), with around a third of cases having scalp involvement. 37,77 Progression to systemic LE is uncommon (< 10%) in those presenting purely with skin lesions. 78 Clinical features include

8 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. 489 Table 3 Summary of the main clinical and histopathologial characteristics for each primary cicatricial alopecia entity (Table adapted from Sellheyer and Bergfeld 9 ) Epidemiology Clinical features Investigations associations Histopathology Lymphocytic group Lichen planopilaris (LPP) More common in women; adults Chronic cutaneous lupus erythematosus (CCLE) More common in women; adults Central scalp location; multifocal patches or diffuse confetti-like pattern; perifollicular erythema and hyperkeratosis; predominant activity at EDGE of alopecia patch. Nonscalp lichen planus may coexist Central scalp location; solitary or multiple plaques with diffuse erythema, scale and follicular plugging followed by progressive atrophy, telangiectasia and dyspigmentation; predominant activity in CENTRE of alopecia patch. Nonscalp lesions in 80 90% cases. 37,69 Risk of systemic disease low (< 10%) in those initially presenting with CCLE 78 Consider LFT, hepatitis B & C serology Exclude drug-induced LPP ANA, ENA, dsdna, U&E, LFT, urinalysis, blood pressure Lymphocytic infiltrate centred on infundibulum and isthmus; interface dermatitis (lichenoid > vacuolar) present; prominent cytoid bodies; loss of sebaceous glands (early); superficial perivascular pattern of inflammation only mucinours perifollicular fibroplasia; 116 no peri-eccrine inflammation; no dermal mucin. VVG stain: Superficial, wedge-shaped scar; elastin fibres preserved in interfollicular dermis. 43 IMF: Globular IgM (± fibrinogen) on cytoid bodies Lymphocytic infiltrate involving the infundibulum, isthmus and interfollicular epidermis; interface dermatitis (vacuolar > lichenoid) present; superficial and deep perivascular and peri-eccrine inflammation; follicular plugging; thickened basement membrane; moderate dermal mucin. VVG stain: Diffuse dermal scarring with loss of elastin fibres. 43 IMF: Granular linear deposits of IgG and C3 along epidermal and follicular BMZ (lupus band); IMF positive in % cases 44,79,117 Pseudopelade of Brocq (PB) More common in women; adults Flesh-coloured (atrophic) patches; likened to footprints in the snow ; 82 no visible inflammation; may coalesce into larger irregular patches. Symptoms usually absent Usually none required Lymphocytic infiltrate around the infundibulum and isthmus (may be sparse or absent); no interface changes; superficial (or absent) perivascular pattern of inflammation; concentric lamellar fibroplasias often marked; absent sebaceous glands but arrector pili muscles remain intact. VVG stain: Thickened elastin fibres in hyalinized dermis; wide fibrous tracts with intact elastic sheath. 43 Central centrifugal cicatricial alopecia (CCCA) More common in women; adults; African descent Starts over vertex crown; slowly progressive centrifugal spread; skin noninflamed and flesh-coloured; individual or grouped hairs may survive within zones of scarring; papules or pustules may be present (particularly at the active MARGIN). Symptoms usually absent Possible association with traumatic hair-care practices. 118,119 IMF: Negative Lymphocytic infiltrate around the infundibulum and isthmus (may be sparse or absent); no interface changes; superficial (or absent) perivascular pattern of inflammation; concentric lamellar fibroplasias often marked; premature desquamation of the IRS (early); 48,120 absent sebaceous glands. VVG stain: same staining pattern as PB. 43 IMF: Negative

9 490 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. Table 3 (Continued) Epidemiology Clinical features Investigations associations Histopathology Alopecia mucinosa (AM) All ages Polymorphous skin lesions erythematous papules, patches or plaques; follicular openings often prominent and devoid of hairs; patchy or diffuse alopecia; mucinous material may sometimes be expressed from follicular openings with firm pressure; initial hair loss may be nonscarring. May involve any part of integument; predilection for scalp and eyebrows Keratosis follicularis spinulosa decalvans (KFSD) More common in males; onset in childhood; X-linked 95 Onset of keratosis pilaris on face, trunk and limbs in infancy; patchy alopecia with perifollicular erythema and scale; progressive scarring alopecia during later childhood; reduced disease activity around puberty; 94 infective exacerbations (pustules) common; loss of eyebrows and eyelashes (early). Associated with photophobia, corneal dystrophy, palmoplantar keratoderma and atopy Neutrophilic and mixed groups Folliculitis decalvans (FD) Adults Single or multifocal patches; expanding rim of painful folliculitis; thickened hypertrophic scarring; hair tufting ( doll s hair ); follicular pustules and scale common; predominant activity at EDGE of alopecia patch Dissecting cellulitis of the scalp (DCS) More common in black males Multiple painful interconnecting scalp nodules with overlying alopecia; nodules often fluctuant and may discharge purulent material; sinus tracts present; initial hair loss nonpermanent due to switch in hair cycle from anagen to telogen; hypertrophic scarring (late). Associated with acne conglobata and hidradenitis suppurativa (follicular occlusion triad) and with arthritis. 51, Risk of SCC in long-standing cases; 126 tinea capitis may mimic DCS 34 Rule out associated malignancy. LONG-TERM FOLLOW-UP REQUIRED 88,89,91 Ophthalmology assessment; 121 genetic counselling Lymphocytic infiltrate involving entire follicle; no interface changes; superficial and deep perivascular inflammation; atypical lymphocytes and epidermotropism should prompt further evaluation to rule out malignancy; mucinous degeneration of sebaceous gland and ORS the entire follicle may be affected. VVG stain: Staining pattern unknown. IMF: Negative Acute lesions show epidermal oedema with neutrophils; replaced later by a lymphocytic mixed infiltrate involving the infundibulum and isthmus; no interface changes; superficial perivascular pattern of inflammation; some perifollicular deposition of mucin (late). VVG stain: Staining pattern unknown. IMF: Negative MC&S (bacterial and fungal) Neutrophilic infiltrate early in disease course, replaced later by lymphocytes and plasma cells; perifollicular and intrafollicular inflammation with developing abscess formation; no sinus tracts; variable dermal fibrosis; follicular plugging. VVG stain: Absent from fibrous tracts and interfollicular dermis (late). IMF: Negative MC&S (bacterial and fungal); Follicular occlusion; early neutrophilic infiltration skin biopsy culture 34 becoming mixed later on; infiltrate typically located deep in the perifollicular and interfollicular dermis and subcutis; deep abscess formation; sinus tracts are characteristic; fibrosis prominent around the fibrous tracts. VVG stain: Absent from fibrous tracts and interfollicular dermis (late). IMF: Negative

10 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. 491 Table 3 (Continued) Epidemiology Clinical features Investigations associations Histopathology Acne keloidalis nuchae (AKN) More common in black males Characteristic location on occipital scalp and neck; firm follicular papules that may coalesce into fibrous nodules and plaques; secondary infection common (pustules and crusting). May be painful. Mechanical irritation suggested as possible predisposing factor; 127,128 tinea capitis may mimic AKN 32 MC&S (bacterial and fungal) Mixed infiltrate of lymphocytes and neutrophils located in the perifollicular dermis and within the follicle; granuloma formation; perifollicular abscess formation; no sinus tracts; perifollicular lamellar fibrosis seen early, with hypertrophic scarring later on; follicular plugging. (Note: in-growing hairs not a feature of AKN). 50 Acne necrotica varioliformis (ANV) Erosive pustular dermatosis of the scalp (EPDS) Adults Itchy and painful lesions found on the frontal hairline and parietal scalp; characteristic lesions are oedematous, umbilicated papulopustules that undergo central necrosis, occur in crops and heal with varioliform scars; lesions often quickly excoriated; exacerbated by stress. 129 The face, eyebrows, neck and chest (seborrhoeic areas) may also be involved Elderly Thick crust overlying erosions and pustules; vertex scalp location; balding and sun-damaged skin; often history of preceding scalp trauma. Lesions usually asymptomatic. Risk of secondary carcinoma; 130 fungal kerion may mimic EPDS. 36 Rule out cicatricial pemphigoid with IMF VVG stain: Absent from fibrous tracts and interfollicular dermis (late). IMF: Negative MC&S (bacterial and fungal) Early acneiform follicular dilatation, lymphocyte exocytosis, follicular spongiosis and perifollicular oedema with a mixed infiltrate of lymphocytes and neutrophils; no abscess formation; no sinus tracts; single cell necrosis progressing to confluent cell necrosis throughout the follicle. VVG stain: Absent from fibrous tracts and interfollicular dermis (late). IMF: Negative MC&S (bacterial and fungal) Histopathology nonspecific; mixed infiltrate of lymphocytes and neutrophils throughout epidermis, hair follicle, dermis and subcutis; epidermal atrophy; foreign-body giant cells; arrector pili muscles remain intact. VVG stain: Absent from fibrous tracts and interfollicular dermis (late). IMF: Negative VVG, Verhoeff van Gieson; IMF, immunofluorescence; BMZ, basement membrane zone; ANA, antinuclear antibodies; ENA, extractable nuclear antigens; dsdna, double-stranded DNA; U&E, urea and electrolytes; LFT, liver function tests, MC&S, microscopy, culture and sensitivities; IRS, inner root sheath; ORS, outer root sheath; SCC, squamous cell carcinoma.

11 492 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. Fig 8. Classic lichen planopilaris (LPP). (a) Loss of follicular ostia with active disease at the expanding edge of the lesion. Perifollicular erythema and follicular hyperkeratosis are typical signs in active LPP. (b) Close-up view of perifollicular erythema and hyperkeratosis. (c) Dermatoscopy view showing loss of follicular ostia and follicular hyperkeratosis. (d, e) Horizontal and vertical histopathology sections showing a perifollicular lichenoid interface dermatitis involving the distal follicle. Haematoxylin and eosin; original magnification: (d) 200, (e) 100. (f) Cytoid bodies highlighted by direct immunofluorescence. Fig 9. Lichen planopilaris variants. (a) Band-like recession of frontal hairline in frontal fibrosing alopecia. Note the loss of eyebrows. (b) Close-up view showing the follicular rash of Graham Little syndrome (GLS). (c) Nonscarring axillary alopecia in GLS. (d) Fibrosing alopecia in a pattern distribution.

12 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. 493 Fig 10. Chronic cutaneous lupus erythematosus (CCLE). (a) Scalp CCLE with predominant inflammation in the centre of the lesion. (b) Lesion of CCLE on the face. (c) Dermatoscopy of a 2-month old patch of CCLE showing erythematous dots within follicular openings. (d) Dense perifollicular lymphocytic infiltrate (haematoxylin and eosin; original magnification 20). (e) Horizontal section through deep dermis showing a vacuolar interface dermatitis, concentric lamellar fibrosis and peri-eccrine inflammation (haematoxylin and eosin; original magnification 200). (f) Lupus band on direct immunofluorescence. diffuse erythema and scale, followed by progressive atrophy, telangiectasia and dyspigmentation. 79 The most pronounced inflammatory activity is usually observed in the centre of the plaque of alopecia. Plaques may be either solitary or multiple and are often found in a central distribution on the scalp. In early CCLE dermatoscopy shows a typical red dot pattern of the follicular openings (Table 2; Fig. 10c). 27,28 Pseudopelade of Brocq Controversy exists as to whether pseudopelade of Brocq (PB; Fig. 11) is a disease entity in its own right or just the endstage appearance of a different scarring process (e.g. LPP, CCLE). 80,81 Plaques are usually ivory-white to flesh-coloured and slightly atrophic. Multiple, variably sized plaques, distributed mainly over the vertex, are typical ( footprints in the snow ) 82 and may fuse into larger, irregularly shaped areas of alopecia. Symptoms and clinically visible inflammation are usually absent. 80 Central centrifugal cicatricial alopecia CCCA (Fig. 12) is characterized by a noninflammatory scarring alopecia of the central scalp. It starts on the vertex and crown and spreads symmetrically and centrifugally. The hair loss of CCCA is often incomplete, with some individual or grouped hairs remaining unaffected within the area of scarring. The scalp skin is usually soft, flesh-toned 7 and without clinical evidence of inflammation. Symptoms are usually absent. 48,49 Alopecia mucinosa Alopecia mucinosa (AM; Fig. 13) may occur at any age and at any body site; however, AM has a predilection for the head and neck, and in particular the scalp and eyebrows. 83 Typical lesions include erythematous follicular papules and indurated plaques, with conspicuous follicular openings that are usually devoid of hairs. However, other morphologies have been described AM may be idiopathic (primary AM) or associated with an underlying lymphoproliferative disorder (secondary AM). 88 At present, the disease course and prognosis, and ultimately the differentiation of primary AM from secondary AM, cannot be predicted using current clinical and pathological criteria Long-term follow-up is therefore mandatory in all cases. Several authorities consider AM in adults almost always to indicate the presence of cutaneous T-cell lymphoma. 92 Keratosis follicularis spinulosa decalvans KFSD (Fig. 14) begins in infancy with progressive development of keratosis pilaris on the face, trunk and limbs. Loss of

13 494 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. Fig 11. Pseudopelade of Brocq. (a) Characteristic noninflamed irregular patch of alopecia. (b) Histopathology examination reveals minimal absent inflammation and follicular scars (haematoxylin and eosin; original magnification 20). Fig 12. Central centrifugal cicatricial alopecia. Centrifugally spreading alopecia with no clinical signs of inflammation (from Whiting, 106 courtesy of Canfield Publishing). Fig 13. Alopecia mucinosa (AM). (a) Multiple plaques of AM on the scalp. (b, c) Histopathology shows intrafollicular mucin deposition. (b) Haematoxylin and eosin; original magnification 200; (c) alcian blue; original magnification 200. eyebrows is seen early in the course of the disease. A progressive scarring alopecia develops later in childhood. Variable degrees of inflammation, follicular hyperkeratosis and atrophy are seen within areas of either patchy or diffuse hair loss. Secondary bacterial infections are common and are heralded by the appearance of crops of new scalp pustules. Photophobia,

14 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. 495 Fig 14. Keratosis follicularis spinulosa decalvans (KFSD). (a) Perifollicular hyperkeratosis is often prominent in KFSD. (b) Loss of eyebrows in KFSD. Fig 15. Folliculitis decalvans (FD). (a) Scarring, scale, follicular pustules and hair tufting characteristic of FD. (b) Hair tufting (tufted folliculitis). (c) Dermatoscopy view shows tufting and coiled capillaries. (d f) Histopathology reveals hair tufting and hair follicle destruction with a dense neutrophilic infiltrate and foreign-body giant cells. Haematoxylin and eosin; original magnification: (d) 20, (e) 100, (f) 200. corneal dystrophy, palmoplantar keratoderma and atopy are associated with KFSD. 93,94 Around puberty a reduction in disease activity is noted and hair loss slows or stops. 66,95,96 Folliculitis decalvans tufted folliculitis FD (Fig. 15) is characterized by a progressive scarring alopecia resulting from a destructive, purulent folliculitis 97 (N.B. Tufted folliculitis appears to represent a variant of FD and the term will be used synonymously with that of FD). 98,99 The vertex is the most commonly affected site. Patches may be single or multifocal and comprise an expanding rim of painful folliculitis that eventually reveals a central area of scarring. 97 This scarred zone is often hypertrophic, which contrasts with the usually atrophic scarring found in CCLE and LPP. Follicular pustules and crusting are prominent and tufts containing mul-

15 496 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. Fig 17. Acne keloidalis nuchae (AKN). (a) Mild moderate AKN with numerous firm follicular papules over the occipital scalp. (b) Large keloid-like area of scarring seen in severe AKN. Fig 16. Dissecting cellulitis of the scalp. (a) Multiple fluctuant scalp nodules. (b) Dense neutrophilic inflammation with follicular destruction (haematoxylin and eosin; original magnification 20). tiple hairs are often seen emerging from a single dilated follicular orifice ( doll s hair ). 29, CAUTION Fungal infections may mimic PCA. Always take samples for culture if scale, pustules or discharge are present Dissecting cellulitis of the scalp DCS (Fig. 16) manifests as multiple enlarging painful and fluctuant nodules and abscesses on the scalp that interconnect via sinus tracts. A purulent material may be discharged either spontaneously, or with firm pressure over lesional skin. 11 The condition is associated with hidradenitis suppurativa and acne conglobata. It is thought that follicular occlusion is one element in the pathogenesis of all three disorders, although the genesis of the inflammatory focus remains obscure. 51 DCS tends to runs a progressive course that eventually results in marked hypertrophic scarring and permanent hair loss. Acne keloidalis nuchae A chronic inflammatory folliculitis, AKN (Fig. 17) commonly involves the occipital scalp resulting in permanent hair loss and scarring. The condition tends to occur preferentially in young black men, although AKN in black women 52 and white men has been described. Lesions start as firm follicular papules that coalesce into larger, keloid-like plaques. Secondary infection is common and is suggested by pustule formation, increased pain and discharge. 50 Acne necrotica varioliformis Acne necrotica varioliformis (Fig. 18) is characterized by crops of follicular lesions, usually involving the parietal scalp and frontal hair line, which heal with scarring. Other areas affected may include the face, eyebrows, neck and chest. The lesions typically comprise oedematous, umbilicated papulopustules that undergo central necrosis, crust over and then slowly heal, leaving varioliform scars. Most lesions are excoriated and may be painful or itchy Erosive pustular dermatosis Erosive pustular dermatosis (Fig. 19) was defined by Burton et al. as a chronic extensive pustulation confined to the scalp of an elderly person, and leading to erosion and scarring alopecia. 57 A typical patient with EPD is elderly, balding and shows signs of chronic sun damage to the scalp. Asymptomatic areas of thick crust are usually present that, when

16 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. 497 Fig 18. Acne necrotica varioliformis (ANV). (a) Moulage of ANV. (b, c) Typical lesions of ANV. Fig 19. Erosive pustular dermatosis of the scalp (EPD). (a) Crusted and eroded lesion of EPD on the bald scalp of an elderly patient. (b) Nonspecific histology showing eroded skin with a dense mixed inflammatory infiltrate (haematoxylin and eosin; original magnification 100). removed, reveal moist erosions, pustules and scarring hair loss. 56,58 Step 3. What does the histology show? See Flowchart 2, (Fig. 6), Figs 8 19 and Table 3. Once secondary causes of cicatricial alopecia have been excluded, the most important histopathological challenge is to identify the predominant inflammatory infiltrate. 9,12 14,25,105 This will aid disease classification and help to narrow the differential diagnosis. Flowchart 2 (Fig. 6) can be used as a rough guide to formulating a histological differential diagnosis. Table 3 can then be used to review specific histological features. CAUTION Some conditions classified into a certain histological subgroup may, at some point during the course of the disease, have a different predominant infiltrate to the main group to which it has been classified. For example, acute lesions of KFSD often show a neutrophil-predominant infiltrate early in the disease course (Table 3). This must be kept in mind when interpreting the pathologist s report.

17 498 Diagnosis of primary cicatricial alopecia, M.J. Harries et al. Histopathology tips in primary cicatricial alopecia 1 Most pathologists are unfamiliar with scalp histopathology. Do not be afraid to ask for an expert pathology review. 2 Within the lymphocyte-predominant subgroup the most common question asked is whether the diagnosis is that of CCLE or LPP. This is because these conditions are the two most commonly encountered diseases within the subgroup, and invite both common and distinct therapeutic approaches. Also, differentiating one disease from another on clinical grounds alone can be difficult. Important histopathological differences do exist and identification of these can usually secure a diagnosis: 44 CCLE displays both superficial and deep perivascular and peri-eccrine inflammation, and the dermis contains moderate amounts of mucin. In LPP, deep periadnexal inflammation and dermal mucin are absent. 9,14 Diagnostic power can be further increased by the addition of immunofluorescence studies (Figs 8f,10f; Table 3) Current histopathological techniques can readily differentiate between lymphocyte-predominant and neutrophil-predominant subgroups of PCA. However, Mirmirani et al. found that within these histopathological subgroups it was not possible to differentiate consistently clinically distinct disease (e.g. LPP, FFA, CCCA and PB in the lymphocyte-predominant subgroup) from the histopathology features alone. 22 Although this study was not a true representation of real life (i.e. it excluded cases of CCLE), it does highlight the importance of good clinicopathological correlation when formulating a diagnosis in PCA. Close communication between pathologist and clinician will maximize the chance of an accurate diagnosis in these disorders. Step 4. Have you reached a working diagnosis? By this point you should have: (i) confirmed that your patient has scarring hair loss; (ii) excluded secondary causes of scarring alopecia; (iii) determined the predominant inflammatory infiltrate on histopathology; (iv) reviewed the clinical and pathological findings and formulated a short-list of possible diagnoses; and (v) reviewed the specific features of each disease (Table 3; Figs 8 19) to determine the final diagnosis. You should now have an accurately diagnosed case of PCA. The next hurdle is how to treat the patient. For this, you may wish to consult our previous review on treatment options in PCA. 4 If you still cannot make a diagnosis, don t worry. Even for the most experienced clinicians, PCA can at times be impossible to diagnose. In this situation cicatricial alopecia of uncertain cause would be an entirely reasonable statement. If the hair loss is still active then follow-up assessment with repeated pathology examination is advised. Referral to a clinician with a specialist interest in hair disorders is a sensible option at any time throughout the diagnostic and treatment process as, for the hair follicle of your patient, rapid initiation of effective therapy is indeed a matter of life and death : any postponement of well-selected therapy (often because a clear-cut working diagnosis has not been reached quickly enough) will increase the level of irreversible hair follicle damage. Conclusion PCAs are an important group of disorders that result in scarring and permanent hair loss. Accurate diagnosis is the vital first step in their successful management. Although by the time most patients are seen permanent follicular damage has occurred; treatment is still required to stop ongoing inflammation and halt further hair loss. Also, the clinically visible extent of scarring is not always a reliable indicator of the actual level of irreversible stem cell damage and subsequent hair follicle destruction. Thus, early initiation of therapy, aided and encouraged by fast and accurate diagnosis, may sometimes still allow hair follicles with residual repair potential to recover from inflammatory damage. Only through correct diagnosis and appropriate management can we hope to minimize the often marked physical and psychological impact that these conditions have on our patients. Acknowledgments Writing of this review was made possible in part by the Geoffrey-Dowling Fellowship from the British Association of Dermatologists to M.J.H., a grant from the University of Lübeck Research Focus Programme on Autoimmunity to R.P. and a grant from the Cicatricial Alopecia Research Foundation (CARF) to M.J.N. and R.P. References 1 Hadshiew IM, Foitzik K, Arck PC et al. Burden of hair loss: stress and the underestimated psychosocial impact of telogen effluvium and androgenetic alopecia. J Invest Dermatol 2004; 123: Paus R, Olsen E, Messenger A. Hair growth disorders. 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Am J Dermatopathol 2006; 28: Headington JT. Cicatricial alopecia. Dermatol Clin 1996; 14: Sperling LC. Scarring alopecia and the dermatopathologist. J Cutan Pathol 2001; 28: Sperling LC, Cowper SE. The histopathology of primary cicatricial alopecia. Semin Cutan Med Surg 2006; 25:41 50.