Cytokeratin 75 expression in central,centrifugal, cicatricial alopecia – new observations in normal and diseased hair follicles

Background: Premature desquamation of the inner root sheath (IRS) is an important histological marker for central, centrifugal, cicatricial alopecia (CCCA), and an inherently defective IRS may be responsible. Cytokeratin 75 (K75; formerly K6hf) is an appealing candidate for study because K75 is specifically expressed in the companion layer of the hair follicle, the interface for IRS desquamation. Also, K75 abnormalities have been found in other hair diseases bearing similarities to CCCA. Methods: We used a commercially available antibody to K75 on formalin‐fixed, paraffin‐embedded tissue from clinically and histologically “normal” scalp (n=9); clinically diseased scalp from patients with CCCA (n=15); and clinically “normal” scalp from patients with CCCA (n=6). Results: K75 expression disappears during the process of IRS desquamation, and loss of expression begins even when IRS desquamation is in its incipient phase. Also, K75 has a characteristic pattern of expression in telogen follicles. Conclusions: K75 expression is closely associated with the process of desquamation of the IRS. This process occurs prematurely (below the isthmus) in many follicles from patients with, but not without, CCCA. K75 expression highlights premature desquamation of the IRS in CCCA, but may not be directly involved in disease pathogenesis. Sperling LC, Hussey S, Sorrells T, Wang J‐A, Darling T. Cytokeratin 75 expression in central, centrifugal, cicatricial alopecia – new observations in normal and diseased hair follicles.     

'A detective look' at hair biopsies from African-American patients

Background A patient’s ethnicity can be an important clue in the diagnosis of scarring alopecia as some disorders such as traction alopecia (TA) and central centrifugal cicatricial alopecia (CCCA) are more prevalent in or exclusive to African‐Americans. Objectives To perform a retrospective review of 60 scalp biopsies from African‐American patients including 25 cases of CCCA, 22 cases of TA, five cases of frontal fibrosing alopecia, three cases of discoid lupus erythematosus, three cases of hair breakage and two cases of alopecia areata. Methods Serial horizontal and vertical sections were examined. Results Features characteristic of the African‐American scalp include: golf club‐shaped bulb, elliptical shape of the hair shaft, asymmetrical outer root sheath and paired grouping of hair follicles. Clues to the diagnosis of CCCA include: premature desquamation of the inner root sheath, goggles and naked hair shafts in fibrous streamers. Diagnosis of TA is suggested by preserved sebaceous glands along with follicular miniaturization and drop‐out. Conclusions The clues reported here aim to help the dermatopathologists to: recognize at a glance that they are dealing with a scalp biopsy from an African‐American patient; make the most probable diagnosis by connecting the clues (even if only vertical sections are present); and understand the morphological basis for the susceptibility of the African hair to damage.     

The follicular degeneration syndrome in black patients. 'Hot comb alopecia' revisited and revised.

BACKGROUND--The history, physical examination, and histologic findings in 10 black women with a common, distinctive form of scarring alopecia (formerly called hot comb alopecia) were retrospectively studied. A detailed history of hair care habits was obtained, and scalp biopsy specimens were examined after both vertical and transverse sectioning. OBSERVATIONS--Poor correlation is noted between the usage of a hot comb and the onset or progression of disease. The earliest observable histologic abnormality is the premature desquamation of the inner root sheath. In severely affected follicles this is followed by a chain of histologic events leading to complete follicular degeneration. CONCLUSIONS--The term follicular degeneration syndrome (FDS) is proposed for this clinically and histologically distinct form of scarring alopecia. Historical information is incompatible with the hypothesis that hot comb usage causes the alopecia. It remains unclear whether the use of any of a variety of hair care products and techniques plays a role in the pathogenesis of this condition. Premature desquamation of the inner root sheath serves as a histologic marker for FDS follicular degeneration syndrome, and may be an important pathogenetic factor.     

Cytokeratin 15 expression in central, centrifugal, cicatricial alopecia: new observations in normal and diseased hair follicles

Background: Cytokeratin 15 (CK15) is a useful marker for the bulge zone (BZ) and has been used to examine follicles in cicatricial alopecia. We studied the expression of CK15 in hair follicles of patients with central, centrifugal, cicatricial alopecia (CCCA) in an attempt to define BZ integrity. Methods: A commercially available antibody to CK15 was used on formalin‐fixed, paraffin‐embedded tissue from clinically and histologically ‘normal’ scalps, clinically diseased scalps from patients with CCCA and clinically ‘normal’ scalps from patients with CCCA. Results: In both normal and diseased follicles, CK15 expression was closely linked to anatomical zone cellular morphology. Normal and abnormal inner root sheath (IRS) desquamation occurred in concert with predictable cellular morphological changes and CK15 expression. In most abnormal follicles, once the IRS desquamated, the morphology of BZ epithelium changed and CK15 expression disappeared. Conclusions: CK15 highlights BZ cells in normal human follicles, but may be unreliable for this purpose in diseased follicles. CK15 should not be the sole marker for studying stem cells in cicatricial alopecia because any disease‐induced structural changes could alter CK15 expression. More sophisticated studies of stem cells will be required to reliably define their role in the pathogenesis of cicatricial alopecia. Sperling LC, Hussey S, Wang J, Darling T. Cytokeratin 15 expression in central, centrifugal, cicatricial alopecia: new observations in normal and diseased hair follicles.     

Follicular streamers (stelae) in scarring and non-scarring alopecia

Background: Follicular streamers are residual fibrovascular tracts representing the impermanent lower third of the hair follicle below the bulge region. Streamers are generally not counted in transverse alopecia samples as they may represent catagen/telogen (CT) follicles and vellus‐like (VL) follicles, or be mistaken as follicular scars. Design: We evaluated 22 non‐scarring alopecia cases, including alopecia areata (AA) and androgenetic alopecia (AGA), and 22 scarring alopecia cases, including follicular degeneration syndrome (FDS)/central centrifugal cicatricial alopecia and other scarring alopecia (OSA) disorders. We counted terminal follicular streamers found at a deep dermal level (L2) and followed them into a mid‐dermal level at the central follicular unit (FU) to determine their precise derivation. Results: We found streamers in 8/9 AA, 11/13 AGA, 6/12 FDS and 3/10 OSA cases. We counted a total of 74 streamers at L2, including 61 in non‐scarring alopecia cases (p < 0.001). At the more superficial FU level, 72% of streamers corresponded to CT follicles, 25% to VL follicles and 3% to follicular scars. Conclusions: Follicular streamers are found predominantly in non‐scarring alopecia cases. Streamers found at deep dermal or subcutaneous levels should be followed and identified at the FU level in order to obtain accurate follicular counts and follicular ratios needed for non‐scarring alopecia diagnosis.     

Prospective histologic examinations in patients who practice traumatic hairstyling

Objectives Alopecia is the fifth most common dermatologic diagnosis in African‐American patients. Central centrifugal cicatricial alopecia (CCCA) is the most common form of scarring alopecia in this group. This study sought to evaluate clinical and histologic findings in patients without clinical alopecia who use chemical and/or thermal straighteners to determine whether follicular damage is evidenced histologically. Methods Eight African‐American women with no clinical evidence of alopecia or scalp inflammation were included in the study. All participants had engaged in some form of traumatic hair care within the previous month. Participants submitted to clinical photography and 4‐mm punch biopsy. Histologic examination was performed and the characteristics of each case recorded. Results There were no clinical signs of alopecia or inflammation in any patient. Histopathology showed peri‐infundibular lymphocytic inflammation in all patients and mild superficial perivascular lymphocytic inflammation in three. Concentric infundibular fibrosis was observed in each hair follicle in all specimens. One sample showed additional focal peri‐isthmus fibrosis. There was no evidence of complete follicular dropout, follicular epithelial thinning, or premature desquamation of inner root sheaths. The mean number of hair follicles was 4.88 per 4‐mm punch. Hair cycling was consistently within normal ranges. Conclusions Biopsy findings characteristic of CCCA suggest that a clinical prelude exists histologically. Further follow‐up may provide a longitudinal timeframe for the potential progression, halting, or reversal of disease if hairstyling practices are, respectively, continued or discontinued. Central centrifugal cicatricial alopecia is likely to represent a common pathway of inflammation and scarring that can be instigated by traumatic hairstyling practices in genetically predisposed subjects.     

Central centrifugal cicatricial alopecia - an approach to diagnosis and management

Central centrifugal cicatricial alopecia (CCCA) occurs primarily in African-American women and is the most common cause of scarring hair loss in this population. Since the mid 20th century, hair care practices of African-American women have been associated with CCCA, although there is developing evidence that the etiology of CCCA may be multifactorial. Clinically diagnosing CCCA may be challenging because it can resemble female pattern hair loss, alopecia areata, lichen planopilaris, or telogen effluvium. Therapeutic options are limited, thus the goal of treatment is to prevent progression of disease because once scar formation occurs, it is irreversible.     

Trichostasis spinulosa of the scalp mimicking Alopecia Areata black dots

Alopecia areata is a common autoimmune disorder that leads to nonscarring hair loss. Black dots, also called comedo-like cadaver hairs, can be found in almost 50% of alopecia areata patients and indicate disease activity. Trichostasis spinulosa is a follicular disorder resulting from the retention of numerous hairs surrounded by a keratinous sheath in dilated follicles. Trichostasis spinulosa is a relatively common but underdiagnosed disorder of hair follicles. Here, we describe a man with alopecia areata of the eyebrows, androgenetic alopecia and trichostasis spinulosa at the vertex and show how dermoscopy can be useful in distinguishing black dots from Trichostasis spinulosa lesions.     

Increased number of OKT6-positive dendritic cells in the hair follicles of patients with alopecia areata

In 6 patients with untreated alopecia areata in the progressive stage, 6 in the stationary stage, and 6 normal individuals as controls, an in situ analysis of OKT6-positive dendritic cells in hair follicles, and peribulbar and intrabulbar infiltrates was performed using the avidin-biotin-peroxidase method with monoclonal antibodies. In controls, OKT6-positive dendritic cells were distributed only in the upper portions of hair follicles and were not observed in the bulbar area, and the percentage of these cells among all epithelial cells of the hair follicles was 1.0 +/- 0.1% (mean +/- SE). In stationary-stage patients, the distribution and the percentage of positive cells were the same as those for the controls (1.1 +/- 0.1%). In the progressive stage, however, positive cells were distributed in both the upper portions of the hair follicles and the bulbar area, and the percentage of positive cells (4.9 +/- 0.3%) was significantly higher than that of controls. Staining for T, B lymphocytes and T cell subsets in the peribulbar infiltrates revealed a predominance of OKT4-positive cells (the OKT4/OKT8 ratio was from 3:1 to 4:1). This indicates that the number of OKT6-positive dendritic cells increases in the hair follicles of progressive alopecia areata and that these cells may play an important role in cooperation with T cells in the pathogenesis of alopecia areata.     

Characterization of the inflammatory features of central centrifugal cicatricial alopecia

Central centrifugal cicatricial alopecia (CCCA) is a scarring alopecia that primarily affects women of African descent. Although histopathological features of CCCA have been described, the pathophysiology of this disease remains unclear. To better understand the components of CCCA pathophysiology, we evaluated the composition of the inflammatory infiltrate, the distribution of Langerhans cells (LCs), and the relationship between fibrosis and perifollicular vessel distribution. Our data indicate that CCCA is associated with a CD4-predominant T-cell infiltrate with increased LCs extending into the lower hair follicle. Fibroplasia associated with follicular scarring displaces blood vessels away from the outer root sheath epithelium. These data indicate that CCCA is an inflammatory scarring alopecia with unique pathophysiologic features that differentiate it from other lymphocytic scarring processes.     

Syringoma-like sweat duct proliferation in scalp alopecias

We have reviewed a series of 585 scalp biopsies taken for histologic evaluation of hair loss and have looked for syringoma-like eccrine sweat duct proliferation. This feature was found in 6 specimens with scarring alopecia and one each with alopecia areata and female-pattern alopecia. Syringoma-like sweat duct proliferation appears to play no role in the etiology of hair loss.     

'Follicular Swiss cheese' pattern--another histopathologic clue to alopecia areata

Yellow dots are the most useful dermoscopic criterion in the clinical diagnosis of alopecia areata and correspond histopathologically with dilated follicular infundibula. They are found in about 95% of alopecia areata cases and help to differentiate alopecia areata from trichotillomania, telogen effluvium and from scarring alopecias. Histopathology of alopecia areata differs with disease activity and dermatopathologist, therefore, heavily depends on other diagnostic features. Objective of the study was to determine the frequency of dilated follicular infundibula, peribulbar lymphocytic infiltrate, inflammatory infiltrates of lymphocytes and eosinophils within fibrous streamers and a shift to catagen/telogen follicles in alopecia areata. Histopathologic features of 56 specimens of 33 patients were correlated with clinical findings and alopecia areata subtype. Results: 57% of all biopsies showed dilated follicular infundibula, regardless of horizontal or vertical sectioning of the slides. Dilated follicular infundibula showed a maximum occurrence of 66% in the recovery stage of alopecia areata and were seen in 33% of alopecia areata incognita. In conclusion, dilated follicular infundibula, reminiscent of a Swiss cheese in horizontally sectioned slides, is an exceedingly useful criterion in the histopathologic diagnosis of alopecia areata and are of great help in the daily routine to recognize alopecia areata.     

Histopathologic features of alopecia areata: a new look

BACKGROUND: A peribulbar lymphocytic infiltrate is the expected histologic feature of alopecia areata, but it is absent in many scalp biopsy specimens. Other diagnostic criteria are needed. OBJECTIVE: To establish the histologic features of alopecia areata in scalp biopsy specimens taken from different types of alopecia areata, using follicular counts to relate biopsy findings to stages of the disease. METHODS: Fifty consecutive new patients with alopecia areata were studied. Four-millimeter punch biopsy specimens were taken from the scalp in areas of recent, active hair loss; old, inactive hair loss; or recent hair regrowth. Specimens were sectioned horizontally. Terminal and vellus-like hairs were counted. Inflammation and fibrosis around lower and upper follicles were rated. RESULTS: The histopathologic features of alopecia areata were not significantly affected by the sex, age, and race of the patient or by the type, percentage of hair loss, total duration, or regression of alopecia areata. The major factor affecting the histopathologic features was the duration of the current episode of alopecia areata. In the acute stage, bulbar lymphocytes surrounded terminal hairs in early episodes and miniaturized hairs in repeated episodes. In the subacute stage, decreased anagen and increased catagen and telogen hairs were characteristic. In the chronic stage, decreased terminal and increased miniaturized hairs were found, with variable inflammation. During recovery, increasing numbers of terminal anagen hairs from regrowth of miniaturized hairs and a lack of inflammation were noted. CONCLUSIONS: The histopathologic features of alopecia areata depend on the stage of the current episode. Alopecia areata should be suspected when high percentages of telogen hairs or miniaturized hairs are present, even in the absence of a peribulbar lymphocytic infiltrate.     

Histopathologic features of alopecia areata incognito: a review of 46 cases

Background: Alopecia areata (AA) incognito represents a variant of AA characterized by acute diffuse hair thinning. Dermoscopy shows yellow dots and short regrowing hairs. The differential diagnosis with telogen effluvium (TE) and androgenetic alopecia may be difficult. Methods: In order to establish histopathological criteria for the diagnosis of AA incognito, we evaluated retrospectively 92 specimens (46 horizontal and 46 vertical) of 46 patients diagnosed with AA incognito within 1 year. All specimens were assessed for 20 features, including hair counts and follicular ratios. The numbers were compared with 46 control specimens, consisting of 21 cases of TE and 25 cases of androgenetic alopecia. Results: The following main criteria are proposed: (a) preserved number of follicular units and decreased number of terminal follicles; (b) increased number of telogen structures (mean count of 37%) with presence of at least one telogen germinal unit or/and one small telogen follicle (c) decreased terminal:vellus ratio (mean ratio of 3.3 : 1) and (d) dilated infundibular openings. Conclusion: Two histopathologic clues for AA incognito include the presence of dilated infundibular openings and small basaloid aggregates of cells with round, irregular or polygonal shape, lack of hair shaft and no apoptosis in the outer root sheath, corresponding to small telogen follicles. Miteva M, Misciali C, Fanti PA, Tosti A. Histopathologic features of alopecia areata incognito: a review of 46 cases.     

Molecular mechanisms regulating hair follicle development

Clinical conditions causing hair loss, such as androgenetic alopecia, alopecia areata, and scarring alopecia, can be psychologically devastating to individuals and are the target of a multimillion dollar pharmaceutical industry. The importance of the hair follicle in skin biology, however, does not rest solely with its ability to produce hair. Hair follicles are self-renewing and contain reservoirs of multipotent stem cells that are capable of regenerating the epidermis and are thought to be utilized in wound healing. Hair follicles are also the sites of origin of many neoplasias, including some basal cell carcinomas and pilomatricoma. These diseases result from inappropriate activation of signaling pathways that regulate hair follicle morphogenesis. Identification of the signaling molecules and pathways operating in developing and postnatal, cycling, hair follicles is therefore vital to our understanding of pathogenic states in the skin and may ultimately permit the development of novel therapies for skin tumors as well as for hair loss disease. The purpose of this review is to summarize recent progress in our understanding of the molecular mechanisms regulating hair follicle formation, and to discuss ways in which this information may eventually be utilized in the clinic.     

Erworbene Alopezien im Kindesalter

Hair loss and alopecia occur frequently in children. The prevalence of the underlying causes and conditions, treatment options and prognosis differ in part significantly from adulthood. This article focuses on frequent forms of acquired alopecia which are not associated with inflammation or scarring of the scalp. Special attention is given to alopecia areata as the most important entity and to trichotillomania as its most difficult differential diagnosis. Significant forms of diffuse hair loss include anagen-dystrophic and telogen effluvium, androgenetic alopecia and loose anagen hair.     

Diffuse alopecia with stem cell folliculitis: chronic diffuse alopecia areata or a distinct entity?

A 34-year-old woman presented with an 8-year history of slowly progressive diffuse nonscarring alopecia with loss of hair density. Scalp biopsy specimens showed increased miniaturized follicles and an asymmetric wedge-shaped lymphocytic infiltrate concentrated on the stem cell-rich region at the point of entry of sebaceous ducts and at bulge-like regions of multiple follicles. Several hair bulbs emerging at the stem cell compartment also were inflamed, but the hair bulbs in the deeper dermis and subcutis were spared. I speculate whether these findings may represent a stem cell folliculitis similar to the reaction pattern previously observed in graft versus host disease and in androgenetic alopecia. The additional presence of peribulbar lymphocytic inflammation could indicate that the patient had a variant of alopecia areata. The clinical presentation of a slowly progressive diffuse alopecia without progression to clinically recognizable alopecia areata and the prominent lymphocytic inflammation involving the stem cell compartment may prompt a reexamination of similar cases currently classified as chronic diffuse alopecia areata. The concept that lymphocytes can inhibit stem cell function without destroying the stem cells themselves needs consideration.     

Frontal fibrosing alopecia: a survey in 16 patients

BACKGROUND: Postmenopausal frontal fibrosing alopecia (PFFA) was described by Kossard et al. as a progressive recession of the frontal hairline affecting particularly postmenopausal women. Further cases of PFFA have been reported to date, all of them considering it as a variant of lichen planopilaris on the basis of its clinical, histological and immunohistochemical features. OBJECTIVE: To describe clinical features, and response to treatment of 16 cases of frontal fibrosing alopecia diagnosed at our department in the last 6 years. METHODS: In addition to clinical data, biopsies and laboratory tests (antinuclear antibodies, sex hormones, thyroid hormones) were performed in order to rule out other causes of scarring alopecia. Patients were treated with intralesional corticosteroids, finasteride, and minoxidil, depending on the stage of the disease and association to androgenetic alopecia. RESULTS: All patients presented progressive alopecia localized to the frontal and temporal hairlines. Eight patients (50%) had loss of eyebrows, and six patients (37.5%) had axillar alopecia. Ages ranged from 45 to 79. Three of these women were premenopausal. Androgenetic alopecia was evident in seven patients (43.8%). All patients biopsied showed perifollicular lymphocitic infiltrate with lamelar fibrosis limited to the upper portions of the follicle. The progression of the condition stopped in most patients after a variable period on treatment. When treatment was abandoned the alopecia progressed to 'clown alopecia' appearance. DISCUSSION: Cases of Kossard's type scarring alopecia affecting premenopausal women made us consider that this condition is not exclusive of postmenopausal women. Differential diagnosis should take into account conditions like female androgenetic alopecia, fibrosing alopecia in a pattern distribution, alopecia areata, and chronic lupus erythematosus. Except for the pattern of alopecia, lichen planopilaris and frontal fibrosing alopecia are indistinguishable, thus the latter is included as a variant of lichen planopilaris. Although the disease tends to spontaneous stabilization, intralesional and topical corticosteroids, and anti-androgens may stop the progression of the disease and improve the female androgenetic alopecia that usually is associated to FFA.     

Expression of the L-fucose moiety on infrainfundibular follicular keratinocytes of terminal follicles, its decreased expression on vellus and indeterminate follicles of androgenetic alopecia, and re-expression in drug-induced hair regrowth.

The distribution of various glycoprotein molecules on the surface of follicular keratinocytes was studied with a panel of lectins with specificity for various sugar moieties on biopsy specimens from both bald/balding scalp and normal occipital scalp, of 23 patients with androgenetic alopecia as well as on biopsies of normal forearm skin of four patients. The most significant differences between bald and normal scalp biopsy were noted with Ulex europaeus agglutinin I (UEA I). We noted an increased (91.8% +/- 3.1; mean +/- SE) expression of UEA I binding sites on the infra-infundibular follicular keratinocytes in anagen terminal scalp hairs, compared to 28.5% +/- 5.2 in the indeterminate (anagen) hairs of balding scalps, and 23.2% +/- 6.3 in the anagen follicles of vellus fore-arm hairs. By contrast, the telogen hairs demonstrated minimal UEA I staining: 4.0% +/- 0.8, mean +/- SE in telogen scalp hairs, 1.8% +/- 0.5 in telogen hairs of balding scalps (0% in completely bald scalps, in which all the hairs were in the telogen phase), and 1.9% +/- 0.2 in telogen forearm hairs. The percentage of UEA I staining correlated with the length of the infra-infundibular follicles in all cases studied. In three cases of hair regrowth after hair growth promotors, the UEA I staining increased to 80.6% +/- 6.1 in anagen hairs and correlated with increased length of infra-infundibular follicles. Our data indicate that there are 1) marked differences between anagen and telogen follicles in UEA I binding to infra-infundibular follicular keratinocytes; 2) the percentage of UEA I staining reflects the size (length) of the infra-infundibular hair follicle; and 3) the anagen follicles of balding scalps (indeterminate hairs) show UEA I staining resembling that exhibited by anagen follicles of vellus hairs.     

Hair and scalp dermatoscopy

Dermatoscopy is a noninvasive diagnostic tool that allows the recognition of morphologic structures not visible by the naked eye. Trichoscopy (scalp dermatoscopy and videodermatoscopy) is useful for the diagnosis and follow-up of hair and scalp disorders. However, it is not widely used in the management of hair disorders. This review provides updated information from the literature and our experience on the dermoscopic features of the most common hair and scalp disorders. This will enable dermatologists to make fast diagnoses of tinea capitis and alopecia areata, distinguish early androgenetic alopecia from telogen effluvium, and differentiate scarring from nonscarring alopecia.