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.     

The Ludwig pattern of androgenetic alopecia is due to a hierarchy of androgen sensitivity within follicular units that leads to selective miniaturization and a reduction in the number of terminal hairs per follicular unit

Background Hair follicles exist within follicular units (FUs). In utero the central primary hair follicles are surrounded by smaller secondary follicles. Each FU is nourished by a single arborizing arrector pili muscle that attaches circumferentially around the primary follicle with variable attachment to other follicles. Androgenetic alopecia (AA) miniaturizes susceptible scalp hair follicles in a distinctive and reproducible fashion manifesting in different patterns between men and women. Objectives We hypothesized that there is an additional layer to the patterning in AA, with a hierarchy of susceptibility within FUs to AA, and that the diffuse hair loss seen in women with AA is due to a reduction in the number of terminal hairs per FU rather than uniform miniaturization of entire FUs. Methods We compared the mean numbers of FUs and terminal hairs per FU in 4‐mm scalp punch biopsies in 24 women with AA with those in 21 controls. Results There was no significant difference in the number of FUs; however, women with AA had 2·40 terminal hairs per FU compared with 3·38 in the control group (P = 0·0001) associated with a mean increase of 0·6 vellus hairs per FU. Complete miniaturization of all hairs within the FU was not seen. Conclusions Diffuse hair loss in women with AA is due to a reduction in the number of terminal hairs per FU and an increase in the number of vellus hairs. This supports the hypothesis of a hierarchy of susceptibility within FUs to AA. Further investigation is required to ascertain whether secondary and tertiary hair follicles are more susceptible than primary follicles.     

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.     

Quantitative image analysis of hair follicles in alopecia areata.

We took biopsies from similar sites on the scalps of normal controls, normal looking and hair loss areas of patients with alopecia areata. The specimens were sectioned serially and horizontally. We measured morphological parameters, such as the diameter of the hair shaft, the thickness of the inner root sheath, the diameter of the outer root sheath, the irregularity of the outer root sheath and the ratio between the diameters of the hair shaft and the outer root sheath, using a computerized image analysis system. There were significant differences in 5 parameters between hair loss areas and normal controls. The proportions of vellus and telogen hair were significantly higher in the areata areas than in the controls. The 5 morphological parameters and most quantitative-measured parameters of normal-looking areas from patients with alopecia values intermediate between the other groups.     

Androgens and hair growth

Hair's importance in human communication means that abnormalities like excess hair in hirsutism or hair loss in alopecia cause psychological distress. Androgens are the main regulator of human hair follicles, changing small vellus follicles producing tiny, virtually invisible hairs into larger intermediate and terminal follicles making bigger, pigmented hairs. The response to androgens varies with the body site as it is specific to the hair follicle itself. Normally around puberty, androgens stimulate axillary and pubic hair in both sexes, plus the beard, etc. in men, while later they may also inhibit scalp hair growth causing androgenetic alopecia. Androgens act within the follicle to alter the mesenchyme-epithelial cell interactions, changing the length of time the hair is growing, the dermal papilla size and dermal papilla cell, keratinocyte and melanocyte activity. Greater understanding of the mechanisms of androgen action in follicles should improve therapies for poorly controlled hair disorders like hirsutism and alopecia.     

Permanent alopecia after systemic chemotherapy: a clinicopathological study of 10 cases

Anagen effluvium due to chemotherapy is usually reversible with complete hair regrowth. However, there is increased evidence that certain chemotherapy regimens can cause dose-dependent permanent alopecia. The histological features of this type of alopecia and the mechanisms of its origin are not known yet. We discuss the histological features of 10 cases of permanent alopecia after systematic chemotherapy with taxanes (docetaxel) for breast cancer (6 patients), busulfan for acute myelogenous leukemia (3 patients), and cisplatin and etoposide for lung cancer (1 patient). All patients had moderate to very severe hair thinning, which in 4 cases was more accentuated on androgen-dependent scalp regions. Patients complained that scalp hair did not grow longer than 10 cm and showed altered texture. Paired scalp biopsies from the affected scalp areas were obtained and evaluated in serial horizontal and vertical sections. The histology of all specimens was characterized by a nonscarring pattern with a preserved number of follicular units and lack of fibrosis. The hair count revealed decreased number of terminal hairs, increased telogen hairs, and increased miniaturized vellus-like hairs with a terminal to vellus and anagen to telogen ratios of 1:1 and 3.6:1, respectively. There was increased number of fibrous streamers (stelae) in both reticular dermis and subcutis. Arao-Perkins bodies were found in the subcutaneous portions of the streamers. The histological findings of permanent alopecia after chemotherapy are those of a nonscarring alopecia similar to androgenetic alopecia. Dermatopathologists should be aware of this condition as the absence of fibrosis and the presence of miniaturized hairs may be considered as features consistent with a diagnosis of androgenetic alopecia. Hence, these cases could easily be misdiagnosed in the absence of a good clinicopathological correlation.     

Cellular and developmental aspects of androgenetic alopecia

The hair follicle is a highly complex system that can be investigated at many levels and from multiple perspectives. However, underlying the cyclic production of all hair fibres are a set of common developmental processes. Many current investigations of androgenetic alopecia concentrate on the direct influences of hormones on hair follicles at the cellular or intracellular level. This paper attempts to step back from this and consider the process of terminal to vellus transition in androgenetic alopecia in terms of basic cellular and developmental mechanisms. Ideas about the mechanism and timing of follicle size reduction are put forward, but the paper also tries to point out inherent difficulties in the investigation of androgenetic alopecia and important gaps in current knowledge.     

Hair counts from scalp biopsy specimens in Asians.

BACKGROUND: Differences in hair density have been described according to the ethnic background in whites and blacks. Asians are known to have fewer hairs than whites. OBJECTIVE: We performed this study to assess the normal values of hair counts in scalp biopsy specimens from Koreans. METHODS: A total of 35 subjects with clinically normal occipital scalps (13 patients with androgenetic alopecia, 20 with patchy alopecia areata, and 2 healthy volunteers) were included. Horizontal sections of 4-mm punch biopsy specimens from clinically normal occipital scalps were examined at various levels from the papillary dermis to the subcutis, and follicular counts of terminal/vellus hairs and anagen/telogen hairs were obtained. RESULTS: The numbers of total hairs, terminal and vellus hairs, and terminal anagen hairs were significantly lower (P <.05) in Koreans compared with the published data of whites and blacks. Percent ratio of terminal anagen and telogen hairs were similar to whites and blacks. Follicular density was significantly lower (P <.05) in Koreans than in whites and blacks. In Koreans, female subjects had a significantly higher number of terminal hairs than male subjects (P <.05). CONCLUSION: Hair density is significantly lower in Koreans than in whites or blacks. Slight sexual difference exists in follicular counts in Koreans. Our data could be used as a guideline for determining normalcy in interpreting horizontal sections of scalp biopsy specimens from Asians.     

Measuring reversal of hair miniaturization in androgenetic alopecia by follicular counts in horizontal sections of serial scalp biopsies: results of finasteride 1 mg treatment of men and postmenopausal women

Hair regrowth was evaluated by histologic analysis in men and women treated for androgenetic alopecia, by counting follicles in horizontal sections of scalp biopsies. Serial 4mm punch biopsies were taken at baseline and after 12mo of treatment from the transitional area of hair thinning between normal hair and vertex balding in men, and in an area of frontal/parietal thinning in women. Horizontal sections of reticular and papillary dermis were read by one observer, blinded to patient, treatment, and time. All terminal hair bulbs, terminal anagen and telogen hairs, and vellus and vellus-like miniaturized hairs were counted. Twenty-six men aged 18-41y, comprising 14 on finasteride 1 mg daily and 12 on placebo, and 94 postmenopausal women, aged 41-60y, comprising 44 on finasteride 1 mg daily and 50 on placebo, were evaluated. In the male study, the terminal hairs increased from a mean baseline count of 15.5-20.9 after 12mo of finasteride, versus 17.3-18.3 in the placebo patients. The miniaturized hairs decreased from 26.7 to 23.6 with finasteride versus 21.3-20.3 with placebo. The terminal-to-vellus ratio increased more in the finasteride than in the placebo patients, suggesting some reversal of the miniaturization process with finasteride. In the female study, no significant differences in follicular counts were found between the finasteride and placebo groups after 12mo of treatment. Follicular counts in horizontal sections provide an informative adjunct to noninvasive measures used in hair growth studies. Finasteride appears to be capable of reversing hair miniaturization in androgenetic alopecia in young to middle-aged men, but not in postmenopausal women.     

雄秃样纤维性秃发一例

【摘要】 报道1例雄秃样纤维性秃发（FAPD）及其临床病理、皮肤镜和TrichoScan特征,以提高对FAPD的认识。患者男,23岁,前额及头顶部进行性脱发10年,伴局部头发变细、软,偶有头皮瘙痒。皮肤科检查：前额至头顶部头发弥漫性稀疏,前额发际线后移,局部发质细软,脱发区可见部分毛囊角化性丘疹、毛囊周围红斑,未见明显鳞屑。TrichoScan检查：毛发密度明显降低,毳毛比例增加。皮肤镜检查：部分毛囊开口消失,融合性白点征。头皮组织病理检查：毛囊漏斗部、峡部淋巴细胞苔藓样浸润,毛囊周围同心层状纤维化,毛囊结构破坏,毛囊性微瘢痕形成,残留毛囊直径变异度明显增加,可见部分毳毛。诊断：FAPD。FAPD临床易误诊为雄激素性秃发,需及早诊断并治疗。     

Dry dermoscopy in clinical treatment of alopecia areata

Although dermoscopy is conventionally utilized with immersion gel for diagnosis of pigmented tumor, we utilized dry dermoscopy, which is dermoscopy without immersion gel, for clinical treatment of alopecia areata (AA). The scalp skin and hair of a 38-year-old Japanese male, and 23-, 22- and 47-year-old Japanese females with AA, whose normal hair color was black, were examined by dry dermoscopy. Exclamation mark hairs, short hairs, fractured hairs and black dots, all characteristic of AA, were detected by dry dermoscopy of the scalp of the 23-year-old female with ophiasis type AA. In the case of the 47-year-old female with round hair loss on the occipital scalp and diffuse hair loss over the fronto-vertical region, dry dermoscopy was useful for diagnosis of AA based on hair characteristic of AA. After she received corticosteroid pulse therapy with 500 mg of i.v. methylprednisolone on 3 successive days, her hair showed apparent regrowth and disappearance of the abnormal hairs characteristic of AA, evidenced by dry dermoscopy 1 month later. In a case of long-lasting AA in the 23-year-old female, we found a follicular plaque-like appearance at the opened hair follicle pores by dry dermoscopy. Histopathologically, the incompletely differentiated remnant hair shaft was packed in the follicular infundibulum. In addition, regrowing vellus hairs, which were difficult to clinically recognize, were detected by dry dermoscopy. Dry dermoscopy is therefore useful for both diagnosis and follow up of AA.     

Dexpanthenol may be a novel treatment for male androgenetic alopecia: Analysis of nine cases

Androgenetic alopecia also known as pattern alopecia, is a disorder characterized by the gradual onset of the conversion of terminal hairs into vellus hairs. Dexpanthenol has an anti‐oxidative and anti‐inflammatory effect and a cellular repair capability. We present nine male cases who had marked improvement after receiving only systemic dexpanthenol treatment for androgenetic alopecia.     

Immunohistochemical localization of types 1 and 2 5alpha-reductase in human scalp

The predominant form of 5alpha-reductase (5aR) in human scalp is 5aR1. None the less, clinical studies have shown that finasteride, a selective inhibitor of 5aR2, decreases scalp dihydrotestosterone and promotes hair growth in men with androgenetic alopecia. Immunolocalization studies were thus carried out to examine 5aR isozyme distribution within scalp and, in particular, to determine whether 5aR2 might be associated with hair follicles. 5aR2 was localized using both a rabbit polyclonal and a mouse monoclonal antibody. 5aR1 was detected with a mouse monoclonal antibody. The specificity of these reagents was demonstrated both by immunofluorescence and Western blot analyses of COS cells overexpressing human 5aR1 or 5aR2. When cryosections of scalp from men with androgenetic alopecia were stained with antibody against 5aR2, using immunoperoxidase avidin-biotin complex methodology, immunostaining was observed in the inner layer of the outer root sheath and, in more proximal regions of the follicle, in the inner root sheath. Staining was also prominent in the infundibular region of the follicle, with less intense staining extending throughout the granular layer of the epidermis. Some staining was also seen in sebaceous ducts. Similar results were obtained with both the polyclonal and monoclonal 5aR2 antibodies. In contrast, in scalp cryosections stained with antibody to 5aR1, no immunostaining was observed within hair follicles. Intense staining for the type 1 isozyme was, however, detected within sebaceous glands. Our immunolocalization data suggest that the results seen in clinical trials of men with male pattern hair loss treated with finasteride may be due, at least in part, to local inhibition of 5aR2 within the hair follicle.     

Phototrichogram analysis of Japanese female subjects with chronic diffuse hair loss

Hair growth patterns of 101 Japanese female subjects with diffuse, chronic hair loss and 58 healthy Japanese female volunteers were categorized into subgroups using noninvasive quantitative methods after determining the key parameters of hair growth. Phototrichogram was performed at 0 and 48 h after clipping hairs in the parietal region of the scalp. Shaft diameters of the excised hairs were then measured. Multiple regression analysis indicated that hair densities, hair diameters, short hair ratios, and hair growth rates, but not anagen hair ratios, were significant, in order of decreasing importance, for grading female diffuse alopecia. Using cluster analysis, hair growth patterns among subjects complaining of diffuse hair loss were divided into six abnormal groups (n=60), two borderline groups (n=21), and one normal group (n=20). The control subjects judged to be normal by macroscopic observation, actually included two subjects with borderline hair growth patterns and one abnormal subject. Most of the abnormal groups shared features of female androgenetic alopecia. Hair patterns showing a decrease in hair density but without vellus hair change, however, emerged as the most prevalent and distinct pattern of chronic diffuse hair loss among the Japanese female subjects. The phototrichogram, combined with the measurement of hair diameters, is an accurate tool for assessing hair growth patterns, especially in detecting the slight changes indicative of the early phase of diffuse alopecia.     

Trichoscopy for common hair loss diseases: algorithmic method for diagnosis

In recent years, the usefulness of trichoscopy (scalp dermoscopy) has been reported for hair loss diseases. Here, characteristic trichoscopic features of common hair loss diseases are described using a DermLite II pro or Epilight eight. Characteristic trichoscopic features of alopecia areata are black dots, tapering hairs (exclamation mark hairs), broken hairs, yellow dots and short vellus hairs. In androgenetic alopecia (AGA), hair diameter diversity (HDD), perifollicular pigmentation/peripilar sign and yellow dots are trichoscopically observed. In all cases of AGA and female AGA, HDD more than 20%, which corresponds to vellus transformation, can be seen. In cicatricial alopecia (CA), the loss of orifices, a hallmark of CA, and the associated changes including perifollicular erythema or scale and hair tufting were observed. Finally, an algorithmic method for trichoscopic diagnosing is proposed.     

Kenogen in female androgenetic alopecia. A longitudinal study

BACKGROUND: Kenogen indicates the physiological interval of the hair cycle in which the hair follicle remains empty after the telogen hair has been extruded and before a new anagen hair emerges. Kenogen frequency and duration are greater in men and women with androgenetic alopecia (AGA). OBJECTIVE: To study the relationship of kenogen with female AGA. METHODS: A woman with AGA, studied 14 years before, was re-examined for 2 years by the phototrichogram technique. Kenogen was identified when telogen lasted 3 months and shedding left the follicle empty. RESULTS: Kenogen lasted 1-5 months, the longest duration affecting cycles of vellus hairs, and involved more hair follicles (16 vs. 8%) than in the first observation. Cycles of vellus hairs increased in number from 4 to 13%, and cycles with a normal succession of phases decreased from 60 to 32%. CONCLUSIONS: The number of kenogen phases increased in parallel with vellus hairs and the diminished number of normal hair cycles, features that mark AGA aggravation. Kenogen seems to be related also to the progression of female AGA.     

Intradermal injections with 0.5% minoxidil for the treatment of female androgenetic alopecia: A randomized,placebo‐controlled trial

Female androgenetic alopecia is one cause of alopecia in women, although the ideal treatment for this condition remains far from defined. The objective of this study was to evaluate the efficacy and safety of intradermal injections with 0.5% minoxidil for the management of female androgenetic alopecia in a randomized, placebo‐controlled trial. A total of 54 women diagnosed with female androgenetic alopecia were divided into two groups: one group received intradermal injections of 0.5% minoxidil, and the other received 0.9% saline. Biopsy, trichogram, Trichoscan (Tricholog GmbH, Freiburg, Germany), and self‐assessment findings were used to evaluate the outcomes of treatment with minoxidil. In the treated group, there was a significant increase in the terminal‐to‐vellus hair ratio (P < .001) and in the percentage of anagen hairs (P = .048) and an improvement in hair loss and volume (P = .021 and P = .028, respectively). These results show that intradermal injections with minoxidil were more effective than placebo (P < .001) in the treatment of female androgenetic alopecia with a good safety profile.     

Transplants from balding and hairy androgenetic alopecia scalp regrow hair comparably well on immunodeficient mice

Human hair follicles were grafted onto 2 strains of immunodeficient mice to compare the regeneration potential of vellus (miniaturized, balding) and terminal (hairy, nonbalding) follicles from males and a female exhibiting pattern baldness. Each mouse had transplants of both types of follicles from a single donor for direct comparison. Grafted follicles from 2 male donors resulted in nonsignificant differences in mean length (52 mm vs 54 mm) and mean diameter (99 microm vs 93 microm) at 22 weeks for hairs originating from balding and hairy scalp, respectively, corresponding to 400% versus 62% of the mean pretransplantation diameters. Follicles from the female donor transplanted to several mice also resulted in nonsignificant differences in length (43 mm vs 37 mm) for hairs from balding and hairy scalp, respectively, during a period of 22 weeks. The mean diameter of the originally vellus hairs increased 3-fold, whereas the terminal hairs plateaued at approximately 50% of pretransplantation diameter, resulting in a final balding hair volume double that of the nonbalding hairs. This report shows that miniaturized hair follicles of pattern alopecia can quickly regenerate once removed from the human scalp and can grow as well as or better than terminal follicles from the same individual.     

Alopecia totalis incognito

We report an 11-year-old boy with a strong family history of alopecia areata who initially developed alopecia areata with a single circular patch of hair loss on the scalp with exclamation mark hairs at the periphery, which evolved over time into alopecia totalis and then into a novel pattern of hair growth with fine depigmented hair, uniformly 5 mm in length. The hair has not grown any longer over a 48-month follow-up period. Scalp biopsies from the occipital scalp demonstrate dense peribulbar lymphocytic infiltrate and uniform miniaturized secondary vellus hairs. This previously undescribed pattern of alopecia areata is remarkable for total lack of alopecia.