Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity.

Complement signaling is thought to serve as an opsonization signal to promote the phagocytosis of synapses by microglia. However, while its role in synaptic remodeling has been demonstrated in the retino-thalamic system, it remains unclear whether complement signaling mediates synaptic pruning in the brain more generally. Here we found that mice lacking the Complement receptor 3, the major microglia complement receptor, failed to show a deficit in either synaptic pruning or axon elimination in the developing mouse cortex. Instead, mice lacking Complement receptor 3 exhibited a deficit in the perinatal elimination of neurons in the cortex, a deficit that is associated with increased cortical thickness and enhanced functional connectivity in these regions in adulthood. These data demonstrate a role for complement in promoting neuronal elimination in the developing cortex.

A folliculocentric perspective of dandruff pathogenesis: Could a troublesome condition be caused by changes to a natural secretory mechanism?

Dandruff is a common scalp condition, which frequently causes psychological distress in those affected. Dandruff is considered to be caused by an interplay of several factors. However, the pathogenesis of dandruff remains under-investigated, especially with respect to the contribution of the hair follicle. As the hair follicle exhibits unique immune-modulatory properties, including the creation of an immunoinhibitory, immune-privileged milieu, we propose a novel hypothesis taking into account the role of the hair follicle. We hypothesize that the changes and imbalance of yeast and bacterial species, along with increasing proinflammatory sebum by-products, leads to the activation of immune response and inflammation. Hair follicle keratinocytes may then detect these changes in scalp microbiota resulting in the recruitment of leukocytes to the inflammation site. These changes in the scalp skin immune-microenvironment may impact hair follicle immune privilege status, which opens new avenues into exploring the role of the hair follicle in dandruff pathogenesis. Also see the video abstract here: https://youtu.be/mEZEznCYtNs.

Drugs targeting epithelial-mesenchymal transition molecules for treatment of lichen planopilaris.

Primary cicatricial alopecia (PCA), also known as scarring alopecia, comprises a diverse group of hair disorders that cause permanent destruction of the pilosebaceous unit, resulting in disappearance of the follicular ostia. Lichen planopilaris (LPP) is a subtype of primary lymphocytic cicatricial alopecia. There is an urgent need to identify novel molecules that successfully target specific pathogenic pathways in LPP to inhibit and reverse disease progression. Recent studies into LPP pathogenesis have discovered that follicular stem cells undergo epithelial-mesenchymal transition (EMT). We sought to identify drugs that target molecules involved in EMT to repurpose these drugs for treatment of LPP. We identified 8 molecules and 15 drugs that target these EMT molecules. Only four of these drugs (pioglitazone, tofacitinib, barcitinib and apremilast) have been reported in individual cases or case series of patients with LPP and controlled studies are missing. We describe each drug and mechanism of action target EMT in detail. Although previous studies have demonstrated the efficacy of EMT inhibitors in anticancer therapy, there are, to our knowledge, no studies using EMT-attenuating drugs for the treatment of LPP. The treatment molecules discussed in this paper provide a new platform for clinical studies and controlled trials in LPP.

IL-17 Expression in the Perifollicular Fibrosis in Biopsies From Lichen Planopilaris.

BACKGROUND: Lichen planopilaris (LPP) is a primary lymphocytic cicatricial alopecia for which therapy is often ineffective and there is no cure. OBJECTIVES: Looking for a new targetable molecule in the treatment of LPP, we sought to verify whether IL-17 expression is increased in scalp biopsies from patients with active scalp lesions of LPP. METHODS: Horizontal sections of hematoxylin and eosin-stained slides from 40 scalp biopsies of active LPP were retrospectively collected and stained with the monoclonal antibody against IL-17 (Abcam, Cambridge, MA; ab79056, dilution 1:100). Twenty biopsies from patients with chronic telogen effluvium served as controls because of their morphological resemblance to the normal scalp. Statistical analysis was performed using IBM SPSS Statistics for Windows (IBM Corporation, Armonk, NY). RESULTS: The main finding was the positive cytoplasmic expression of IL-17 in the perifollicular fibrosis of the affected follicles in LPP which was statistically significant compared with the controls ( P < 0.0001). The labeled cells were identified as fibroblasts based on their spindle shape and fascicular concentric arrangement in tight perifollicular distribution. Although most of the LPP specimens (n = 35; 87.5%) also revealed cytoplasmic IL-17 expression in the lichenoid inflammatory infiltrate, the results were not statistically significant ( P = 0.1351). CONCLUSION: Our immunohistochemistry results show that blocking the IL-17 inflammatory pathway may interfere with the progression of the perifollicular fibrosis and inflammation in LPP.

Understanding Hormonal Therapies: Overview for the Dermatologist Focused on Hair.

Hormones have an intimate relationship with hair growth. Hormonal replacement therapy is used to treat menopausal symptoms and to provide protection from chronic diseases for which postmenopausal women may be at risk. Additionally, hormonal therapies are prescribed for contraception and treatment of acne. Considering the widespread use of such therapies, there is a demand for further understanding of their implications in hair disorders. This article reviews the specific properties of current estrogen- and progesterone-containing hormonal treatments and their implications for the patient with hair loss. The complexity of the task comes from the paucity of data and discrepancy in the literature on the effect of the specific hormonal-receptor activities.

Folliculitis Decalvans and Lichen Planopilaris Phenotypic Spectrum-A Series of 7 New Cases With Focus on Histopathology.

BACKGROUND: Folliculitis decalvans (FD) and lichen planopilaris (LPP) are classified as neutrophilic and lymphocytic cicatricial alopecias according to the North American Hair Research Society. Recently, a clinical phenotype combining concomitant or sequential features for both was described as a FD LPP phenotypic spectrum (FDLPPPS). OBJECTIVES: To review the most common phenotypic presentation of FDLPPPS with a main focus on histopathology. METHODS: We reviewed retrospectively series of 7 patients with a similar phenotypic presentation with special focus on the histologic pattern. All patients presented with concomitant features for FD and LPP and recalcitrant course unresponsive to topical and systemic immunomodulatory/anti-inflammatory agents. RESULTS: The most common clinical phenotype was that of hairless patches on the vertex with lost follicular ostia and perifollicular scale and the following diagnostic findings: (1) polytrichia; (2) positive bacterial culture for Staphylococcus in over 50% of the samples isolated from pustules and hemorrhagic crusts; (3) "mixed" histologic features for primary cicatricial alopecia including multicompound follicular structures of average 2-5 follicles (follicular packs), atrophy of the follicular epithelium, lymphohistiocytic infiltrate with granulomas, and prominent plasma cells, but absence of neutrophilic infiltrate in all cases except scarce neutrophils in one; and (4) clinical improvement with adjuvant systemic antimicrobials. CONCLUSIONS: The FDLPPPS may be underreported and should be considered in all cases of LPP recalcitrant to treatment. Dermatologists and dermatopathologists should recognize this phenotypic spectrum to guide optimal clinical management consisting of immunomodulatory and anti-inflammatory agents along with systemic antimicrobials.

Seborrheic dermatitis-Looking beyond Malassezia.

Seborrhoeic Dermatitis (SD) is a very common chronic and/or relapsing inflammatory skin disorder whose pathophysiology remains poorly understood. Yeast of the genus Malassezia has long been regarded as a main predisposing factor, even though causal relationship has not been firmly established. Additional predisposing factors have been described, including sebaceous activity, host immunity (especially HIV infection), epidermal barrier integrity, skin microbiota, endocrine and neurologic factors, and environmental influences. Genetic studies in humans and mouse models-with particularly interesting insights from examining the Mpzl3 knockout mice and their SD-like skin phenotype, and patients carrying a ZNF750 mutation-highlight defects in host immunity, epidermal barrier and sebaceous activity. After synthesizing key evidence from the literature, we propose that intrinsic host factors, such as changes in the amount or composition of sebum and/or defective epidermal barrier, rather than Malassezia, may form the basis of SD pathobiology. We argue that these intrinsic changes provide favourable conditions for the commensal Malassezia to over-colonize and elicit host inflammatory response. Aberrant host immune activity or failure to clear skin microbes may bypass the initial epidermal or sebaceous abnormalities. We delineate specific future clinical investigations, complemented by studies in suitable SD animal models, that dissect the roles of different epidermal compartments and immune components as well as their crosstalk and interactions with the skin microbiota during the process of SD. This research perspective beyond the conventional Malassezia-centric view of SD pathogenesis is expected to enable the development of better therapeutic interventions for the management of recurrent SD.

Facial and Extrafacial Lesions in an Ethnically Diverse Series of 91 Patients with Frontal Fibrosing Alopecia Followed at a Single Center.

BACKGROUND: Various facial and extrafacial lesions have been reported in frontal fibrosing alopecia (FFA). Facial papules have been associated with worse prognosis. OBJECTIVES: We sought to detect the prevalence of facial and extrafacial lesions and to analyze their relation to demographic and clinical variables in a large and ethnically diverse series of patients with FFA. METHODS: Charts of patients diagnosed with FFA between January 1, 2015, and December 31, 2017, at the Department of Dermatology, University of Miami, were reviewed retrospectively. RESULTS: 91 patients (87 women and 4 men) met inclusion criteria: 45% (n = 41) were of Hispanic/Latino ethnicity, and 34% (n = 30) were premenopausal. Facial papules were most commonly detected (41% among Hispanic/Latino patients). Significant associations were found between: (1) Hispanic/Latino ethnicity and any FFA-associated facial lesions, facial papules alone, or lichen planus pigmentosus alone, as well as premenopausal status; (2) any FFA-associated facial lesions or facial papules alone and premenopausal status; and (3) Hispanic/Latino ethnicity and simultaneous presence of facial and extrafacial lesions. CONCLUSIONS: There is a significant association among Hispanic/Latino ethnicity, facial papules, and premenopausal status, which may portend a susceptibility to severer disease and prompt early and aggressive treatment in this group.

A New Histologic Pattern in 6 Biopsies From Early Frontal Fibrosing Alopecia.

Frontal fibrosing alopecia (FFA) is an irreversible scarring alopecia with unknown etiology and no cure. The goal is to establish the diagnosis in the early stage, before developing a hairless band of atrophy involving the frontal, temporal scalp and sideburns. Pathology is rarely needed once the disease is clinically apparent. The classic histologic features include follicular dropout with the absence or atrophy of the sebaceous glands and lichenoid lymphohistiocytic infiltrate with concentric layered fibrosis at the upper follicular level. We describe a common pattern that was repeatedly seen in 6 horizontally sectioned scalp biopsies from patients with early presentation of FFA suspected on trichoscopy by the focal presence of peripilar casts around terminal hairs. All biopsies revealed overall preserved follicular architecture with average number of 11 vellus follicles, atrophy of the sebaceous glands, and perifollicular lymphohistiocytic infiltrate involving the outer root sheath of the vellus follicles (n = 5). There was no perifollicular fibrosis of the vellus follicles and no lichenoid inflammation and perifollicular fibrosis of the terminal follicles. This new pattern of "inflammatory vellus involvement" most likely corresponds to an early onset of the disease. The absence of the classic features in such biopsies from early FFA can lead to misdiagnosis.

Adipose Infiltration of the Dermis, Involving the Arrector Pili Muscle, and Dermal Displacement of Eccrine Sweat Coils: New Histologic Observations in Frontal Fibrosing Alopecia.

BACKGROUND: Frontal fibrosing alopecia (FFA) is an irreversible scarring alopecia, and its incidence has reached epidemic size. Immune privilege collapse of the bulge and epithelial mesenchymal transition play a role in the pathogenesis. We have noted adipose tissue in the dermis in several specimens from FFA. OBJECTIVE: Our primary objective was to verify the presence of adipose tissue at the isthmus level in biopsies from FFA. Additional objectives included the presence of deep inflammation and position of the sweat coils. METHODS: Eighty-three histologic specimens of FFA diagnosed at the Dermatopathology Laboratory at the Department of Dermatology, University of Miami, within 3 years were evaluated retrospectively. All biopsies were bisected horizontally and assessed at several levels. Sixty biopsies from androgenetic alopecia served as controls. Statistical analysis was performed using the χ test. A P value of 0.05 or less was considered significant. RESULTS: Sixty specimens met the inclusion criteria for optimal quality and classic diagnostic features. Seventy percent demonstrated fat tissue infiltration at the isthmus level as clusters of cells or small globules versus 23% of the controls. The fat infiltration in the arrector pili muscle (APM) was present in 55% versus 15% of the controls, and the sweat coils were positioned in the reticular dermis in 43% versus 1.7% of the controls. All results were statistically significant (P < 0.0001). When accounting for the simultaneous presence of any of these 3 variables, 30% of the FFA cases had triple positivity, 61.7% had double positivity, and 75% had at least 1 positive variable versus 0%, 15%, and 10%, respectively, of the controls. CONCLUSION: New histologic findings in FFA involve the presence of adipose tissue in the dermis. We believe that the close interaction of the hair follicles and the APM with the adipose tissue may play a role in APM degeneration and in epithelial mesenchymal transition.

Carcinosarcoma of the hand.

Carcinosarcomas are rare malignant tumors derived of both epithelial and mesenchymal elements. Herein, we report an elderly man originally diagnosed with a squamous cell carcinoma of the hand. Upon excision, the tumor was found to be a more aggressive carcinosarcoma. Immunohistochemical stains revealed that the sarcoma component of the lesion was vimentin positive, whereas the primary carcinoma tumor cells were positive for p63 and CK903. Both components were negative for CD34 and D2-40. This tumor was found to have angiolymphatic invasion and eventually metastasized to the axillary lymph nodes and lungs.

Horizontal and vertical sections of scalp biopsy specimens from dermatomyositis patients with scalp involvement.

BACKGROUND: The histologic findings of scalp involvement in dermatomyositis are not well characterized on account of a lack of large series. OBJECTIVE: To systematize the histologic features of scalp involvement in dermatomyositis on horizontal and vertical sections. METHODS: A descriptive, prospective, cross-sectional study recruited 31 patients with pathologically and serologically confirmed dermatomyositis in Mexico City, Mexico, from June 2014 to June 2015. A total of 36 scalp biopsy specimens from 20 patients with scalp involvement in dermatomyositis were processed as 20 vertical and 16 horizontal sections. RESULTS: Dilated capillaries and diffuse mucin deposition were detected in all biopsy specimens, followed by interface dermatitis. Partial or segmental thickening of the basement membrane, hyperkeratosis, atrophic epidermis, and acrosyringeal hypergranulosis with hyperkeratosis were other very common findings. Preserved follicular architecture, with intact or slightly atrophic sebaceous glands, was present in most horizontal sections. There was decreased follicular density, with a terminal-to-vellus ratio of 4:1 and telogen count of 10.3%. Eosinophils were present in 15% and 25% of horizontal and vertical sections, respectively. LIMITATIONS: No special stains performed. CONCLUSION: Scalp involvement in dermatomyositis shows nonscarring pattern on horizontal sections that is consistent with chronic telogen effluvium. Telangiectasia and mucin are universal histologic features; eosinophils and acrosyringeal hypergranulosis with hyperkeratosis are new findings.

Nodular cutaneous amyloidoma of the extremity secondary to chronic granulomatous inflammation in setting of sarcoidosis.

Soft tissue amyloidoma is a rare condition that presents primarily in the abdomen and/or mediastinum and more uncommonly on the extremities. Soft tissue amyloidomas on the extremities have been associated with chronic inflammation, particularly when accompanied by AA-type amyloid deposition as seen in local trauma, surgery, hypertension and diabetes. To our knowledge, this is the first reported case of nodular cutaneous amyloidoma in the setting of systemic and cutaneous sarcoidosis. A 65-year-old woman presented with an asymptomatic subcutaneous nodule above her left lateral malleolus. Histopathology of the lesion showed an inconspicuous epidermis with amorphous eosinophilic material deposited in masses within the entire dermis. Congo red and crystal violet stains were positive. Based on the clinical and pathologic findings she was diagnosed with nodular cutaneous amyloidoma. We hypothesize that this process developed secondary to the chronic granulomatous inflammation of sarcoidosis.

Clinical, dermoscopic, and pathologic features of onychopapilloma: A review of 47 cases.

BACKGROUND: Onychopapilloma is a benign neoplasm of the nail bed and the distal matrix. Although not uncommon in our experience, only up to 32 cases of this tumor have been reported in the literature. OBJECTIVE: We sought to review the clinical, dermoscopic, and pathologic features of onychopapilloma. METHODS: We retrospectively analyzed the clinical features of 47 patients with pathologically confirmed onychopapilloma diagnosed within the last 5 years, and reviewed the published literature. RESULTS: The most common clinical presentation was longitudinal erythronychia (n = 25); followed by longitudinal leukonychia (n = 7); longitudinal melanonychia (n = 4); long splinter hemorrhages without erythronychia, leukonychia, or melanonychia (n = 8); and short splinter hemorrhages without erythronychia, leukonychia, or melanonychia (n = 3), with subungual mass (n = 47) and distal fissuring (n = 11). Pathology was consistent with acanthosis of the nail bed and distal matrix, with matrix metaplasia underlying distal subungual hyperkeratosis. LIMITATIONS: This was a retrospective analysis. CONCLUSION: To our knowledge, our series of onychopapilloma is the largest so far. Among various clinical presentations, longitudinal erythronychia is the most common. Dermoscopy of the free edge of the nail plate showing a small subungual keratotic mass where the band reaches the nail plate margin provides a clue for the diagnosis.

Special Stains and Immunohistochemical Stains in Hair Pathology.

BACKGROUND: Patterns in scalp biopsies can overlap, and distinction may be difficult. OBJECTIVE: To review the current knowledge about the usefulness of special stains and immunohistochemical stains (IHC) for the diagnosis of hair disorders. METHODS: The authors used the search engines PubMED, MEDLINE, and MeSH to retrieve articles on the application of special stains and IHC in hair pathology. RESULTS: The authors selected 65 relevant articles discussing the use of special stains and IHC markers in scalp biopsies, including case reports and original articles. No reviews on the subject were found. Although fungal stains, such as periodic acid-Schiff, are very helpful in the diagnosis of noninflammatory tinea capitis, they may be negative in kerion. Elastic stains may help to diagnose end-stage scarring alopecia on vertical sections. Stains for mucin may help to distinguish lupus erythematosus from lichen planopilaris. Lymphocytic markers may assist in the diagnosis of lymphoma-associated alopecia. CONCLUSIONS: On a practical level, there is no evidence to recommend the routine use of a stain or a panel of stains in hair pathology. No stain can distinguish between nonscarring and early scarring alopecia. Most IHC stains are currently limited to the experimental and research setting.