Histological diversity in hyperkeratotic flexural erythema-Beyond granular parakeratosis?

The term 'hyperkeratotic flexural erythema' (HFE) has been used synonymously with granular parakeratosis (GP), to describe a scaly, typically intertriginous rash associated with contact factors such as benzalkonium chloride. However, clinical HFE can occur without the classical GP histological pattern. We reviewed skin biopsies from 10 patients with clinically diagnosed HFE. A progression of histopathological features is suggested. The absence of histological GP should not exclude the clinical diagnosis of HFE when there is a high index of suspicion.

Hyperkeratotic flexural erythema/granular parakeratosis responding to doxycycline.

Hyperkeratotic flexural erythema (HKFE), also termed granular parakeratosis (GP), is a rare skin condition thought to be linked to a skin barrier dysfunction process, however the exact cause of this is yet to be determined. Management options are varied, with no consensus on treatment. Several previous reports have recorded successful treatment with amoxycillin-clavulanic acid combination. We propose the use of oral doxycycline in addition to topical coconut oil compound as a treatment option in therapy resistant HKFE.

[Confocal line-field OCT]. / Konfokale Line-Field-OCT.

Optical coherence tomography (OCT) and confocal laser microscopy (CLSM) are established non-invasive methods in clinical dermatological routine diagnosis. Whereas CLSM is especially useful to distinguish between nevi and melanoma, OCT is suitable for the diagnosis and differentiation of non-melanoma skin cancer. Line-field confocal optical coherence tomography (LC-OCT) is a new innovative device, which has better cellular resolution than OCT and a higher penetration depth than CLSM. Similar to CLSM, LC-OCT also allows 3D images in real time to be taken. Therefore LC-OCT is very useful for the examination of skin lesions of all kinds, since it unites the features of CLSM and OCT.

Non-malignant conjunctival epithelial masses with ocular surface squamous neoplasia-like optical coherence tomography features.

PURPOSE: To observe and describe the anterior segment optical coherence tomography features of limbally localised non-malignant epithelial mass lesions METHODS: Thirteen patients (age: 66.9 ± 16.3 years) with conjunctival mass suggesting ocular surface squamous neoplasia with biomicroscopic examination were imaged using anterior segment ocular coherence tomography (anterior segment optical coherence tomography)/Cirrus HD-OCT, Model 4000, Carl Zeiss Meditec, Inc., Dublin, CA, and Spectralis HRA + OCT system, Heidelberg Engineering, Vista, CA/. Cases with ocular surface squamous neoplasia-like anterior segment optical coherence tomography (hyperreflective, thickened epithelium and an abrupt transition from normal to abnormal) were included in the study. Maximal thickness of the epithelium was measured. Histological diagnosis was gained from an excisional or incisional biopsy or impression cytology specimens. RESULTS: In six patients (age: 68.5 ± 15.4 years) with ocular surface squamous neoplasia-like anterior segment optical coherence tomography features, the histological diagnosis was other than ocular surface squamous neoplasia (papilloma, parakeratosis and a keratotic plaque with mild dysplasia), and ocular surface squamous neoplasia in seven cases (age: 65.6 ± 18.0 years). The maximal epithelial thickness was between 250 and 859 µm in non-ocular surface squamous neoplasia cases and between 252 and 596 µm in ocular surface squamous neoplasia cases. CONCLUSION: Non-malignant epithelial lesions can mimic ocular surface squamous neoplasia on anterior segment optical coherence tomography.

Ocular manifestations of skin diseases with pathological keratinization abnormalities.

Keratinization means cytodifferentiation of keratinocytes turning into corneocytes in the stratum corneum. Disorders of keratinization (hyperkeratosis, parakeratosis and dyskeratosis) are causing many dermatological diseases, including various types of ichthyoses, pachyonychia congenita, pityriasis rubra pilaris, all subtypes of psoriasis, pityriasis lichenoides, dyskeratosis congenita, leukoplakia and keratosis follicularis, which apart from skin lesions may affect the eye's adnexae causing ectropion, entropion, blepharitis, madarosis, and trichiasis, the ocular surface causing keratitis, conjunctivitis, corneal ulceration and episcleritis, which in turn cause uveitis and various fundoscopic changes (proliferative retinopathy, retinal vasculopathy, macular oedema and birdshot chorioretinopathy). Knowledge of ocular symtoms associated with pathological keratinization is crucial, preventing sight-threatening complications such as corneal perforation, lagophthalmus, phthisis bulbi, retinal neovascularization, retinal vasculopathy and optic nerve atrophy. This review encourages dermatologists to monitor patients for ocular symptoms and encourage ophthalmologists to monitor patients for dermatological symptoms.

Histologic comparison of tumor necrosis factor-α inhibitor-induced psoriasis and psoriasis vulgaris.

BACKGROUND: Tumor necrosis factor-α inhibitor (TNFi)-induced psoriasis is a paradoxic reaction characterized by the development of a psoriasiform rash that mimics idiopathic psoriasis subtypes both clinically and histologically. Few studies have investigated the histologic features of TNFi-induced psoriasis skin lesions, and most of these are limited by inclusion of few specimens. OBJECTIVE: We aimed to characterize histologic features of TNFi-induced psoriasis and identify histologic differences between TNFi-induced psoriasis and idiopathic psoriasis. METHODS: We characterized 60 biopsy specimens obtained from 47 unique patients at a single tertiary care referral center between 2004 and 2016 who developed TNFi-induced psoriasis, and we compared histologic features to those of 85 biopsy specimens from a control group of 85 patients with idiopathic psoriasis. RESULTS: The most common histologic reaction pattern in TNFi-induced psoriasis biopsy specimens was psoriasiform (80.0%). Five histologic parameters were significantly different in TNFi-induced psoriasis biopsy specimens compared with idiopathic psoriasis biopsy specimens: at least 3 dermal eosinophils per histologic section, neutrophils in the stratum corneum, neutrophils in the epidermis, papillary plate thinning, and absence of parakeratosis. LIMITATIONS: Inability to exclude lesion selection bias as a potential reason for some significant histologic differences. CONCLUSIONS: This study supports the idea that histologic differences exist between TNFi-induced psoriasis and idiopathic psoriasis may help distinguish between these conditions, especially for dermal eosinophil counts of 3 or greater.

Poikilodermatous Mycosis Fungoides: Comparative Study of Clinical, Histopathological and Immunohistochemical Features.

BACKGROUND: Poikilodermatous mycosis fungoides (pMF) is characterized by poikiloderma areas, typically involving the major flexural areas and trunk. Its presentation can be generalized or admixed with other forms of MF. Previous studies fail to correlate the clinical presentation with prognosis and laboratory findings. Some reports show pityriasis lichenoides chronica (PLC) preceding the poikiloderma. OBJECTIVES: Correlate prognostic, histopathological and molecular aspects of pMF with its clinical presentation. METHODS: Retrospective analysis of 14 cases of generalized pMF (GpMF), 22 of localized pMF (LpMF) and 17 of pMF admixed with other forms of MF (mix-pMF). RESULTS: Female predominance and lower age at diagnosis was found in all groups compared to classic MF, a high prevalence of PLC-like lesions in the GpMF group and a high rate of hypopigmented lesions in the mix-pMF group. There were 2 deaths within the GpMF group. Histology was similar to previously reported findings, as was the prevalence of CD4 T-cell infiltrate, compared to CD8. The T-cell clonality positivity was lower in the GpMF group, compared to other groups (27% GpMF, 80% LpMF and 100% mix-pMF). DISCUSSION: This is the first article to categorize the different forms of pMF and correlate them with clinical and laboratory findings. The dermatological presentation differs among the groups. There was a high frequency of PLC-like lesions within the GpMF group and of hypopigmented lesions in mix-pMF. The histological and immunohistochemical findings were similar to those previously reported. Aggressive treatments are not recommended due to the good prognosis of all pMF forms. The low positivity of T-cell clonality in the GpMF group should be investigated.

Fluorescent fibre-optic confocal characterization of in vivo epidermal changes in atopic eczema.

BACKGROUND/AIMS: Fibre-optic confocal imaging (FOCI) allows non-invasive visualization of live skin in vivo. A contrast agent, a fluorophore, is injected into the dermis. FOCI images are horizontal optical sections with cellular resolution. The aim was to study in vivo epidermal changes and the cellular structure of keratinocytes in moderate to severe atopic eczema (AE). METHODS: Eight patients with AE with active lesions on the forearms were studied and compared to a control group of six healthy individuals, and two cases of AE without activity. Fluorescein sodium was used as fluorophore. A hand-held fibre-optic laser scanner (Stratum® ) was used. The study included morphometric analyses. RESULTS: The confocal in vivo images identified characteristic features of epidermis and keratinocytes in active AE vs healthy skin controls. FOCI could non-invasively image acanthosis, spongiosis, and parakeratosis in AE. Epidermal oedema and micro-vesicles were visualized. Morphometry based on FOCI demonstrated 14% increased width of keratinocytes of atopic skin vs healthy controls. The epidermal structures and organization in distinctive cell layers were deviant as a result of the disease. CONCLUSIONS: Fibre-optic confocal imaging can visualize essential epidermal structures of atopic eczema directly in vivo, in real-time, and with cellular resolution thus without disturbing the natural state of the skin. FOCI is primarily a research tool, but with a potential to become used in the clinic for non-invasive microscopic diagnosis of AE and monitoring of effect of therapies.

[Clinical heterogeneity of poikilodermatous mycosis fungoides: A retrospective study of 12 cases]. / Hétérogénéité clinique du mycosis fongoïde poïkilodermique : étude rétrospective de 12 cas.

INTRODUCTION: Poikilodermatous mycosis fungoides is a rare and indolent clinical variant of mycosis fungoides (MF). It can be difficult to distinguish from poikilodermatous parapsoriasis, a group of chronical dermatoses that may sometimes progress to MF. We aimed to specify the clinical, histopathological and developmental features of these entities by means of a retrospective study of 12 cases followed in our center. PATIENTS AND METHODS: We identified cases of poikiloderma for which a diagnosis of MF or parapsoriasis was made by the physician. Photographs and histological slides were reviewed, and a final diagnosis of MF was made if the International Society for Cutaneous Lymphoma criteria for the diagnosis of early MF were fulfilled. RESULTS: Twelve patients were included, 10 of whom met of the MF criteria. 5 patients had large poikilodermatous patches or thin, well-defined plaques ; 3 patients had the same lesions associated with classical MF lesions ; finally, 4 patients had widespread ill-defined erythematous lesions in a net-like pattern, described as parakeratosis variegata, including 3 MF. 2 patients with well-defined lesions (one associated with classical MF lesions) progressed to the tumoral stage whereas none of the patients with parakeratosis variegata presented such progression. A total of 5 patients had a high skin phototype (IV and V). Two patients had squamous cell carcinoma on poikilodermatous lesions. DISCUSSION: Our study suggests that poikilodermatous MF covers a heterogeneous clinical spectrum comprising on one hand a presentation of delimited lesions sharing classical MF risk of progression, and on the other, an entity similar to parakeratosis variegata, an entity overlooked in the French nomenclature, which was particularly benign in our small series, raising the question of its affiliation to the MF group. This question merits further investigation in a larger-scale study.

Hyperkeratotic flexural erythema responding to amoxicillin-clavulanic acid therapy: Report of four cases.

Hyperkeratotic eruptions in the flexures, especially in the inguinal region, often pose a diagnostic and therapeutic dilemma. Inguinal keratotic eruptions may be caused by various infections, inflammatory dermatoses, vesico-bullous dermatoses, nutrient deficiencies, medication allergies and other miscellaneous causes such as granular parakeratosis. We hereby report four patients who presented with idiopathic hyperkeratotic erythematous eruptions with a migratory nature involving the inguinal region and occasionally showing the histopathologic features of granular parakeratosis. All four patients showed a dramatic therapeutic response to amoxicillin-clavulanic acid combination. We suggest that 'granular parakeratosis' should be considered as a histopathologic feature rather than the diagnosis. We would prefer to label our cases as 'Hyperkeratotic Flexural Erythema'. We recommend that detailed study of skin microbiome may help identify a possible alteration in skin microbiome contributing to the pathogenesis. We briefly review strategies on characterising the skin microbiome and the latest knowledge surrounding how alterations to the skin microbial populations can contribute to some diseases.

Dermatomyositis: Histopathologic findings of parakeratosis and dermal edema revisited.

The cutaneous manifestations of dermatomyositis range from classical in the case of heliotrope rash and Gottron papules to less common papulosquamous and edematous/vesiculobullous lesions; histopathologic descriptions are dominated by interface dermatitis. We present a case of dermatomyositis with a combination of common and rare skin findings, both clinically and histologically. Increased awareness of papulosquamous and edematous lesions of dermatomyositis can help direct patient care. Although uncommon, confluent parakeratosis and dermal edema can be manifestations of dermatomyositis.

A splice site variant in the SUV39H2 gene in Greyhounds with nasal parakeratosis.

Hereditary nasal parakeratosis (HNPK), described in the Labrador Retriever breed, is a monogenic autosomal recessive disorder that causes crusts and fissures on the nasal planum of otherwise healthy dogs. Our group previously showed that this genodermatosis may be caused by a missense variant located in the SUV39H2 gene encoding a histone 3 lysine 9 methyltransferase, a chromatin modifying enzyme with a potential role in keratinocyte differentiation. In the present study, we investigated a litter of Greyhounds in which six out of eight puppies were affected with parakeratotic lesions restricted to the nasal planum. Clinically and histologically, the lesions were comparable to HNPK in Labrador Retrievers. Whole genome sequencing of one affected Greyhound revealed a 4-bp deletion at the 5'-end of intron 4 of the SUV39H2 gene that was absent in 188 control dog and three wolf genomes. The variant was predicted to disrupt the 5'-splice site with subsequent loss of SUV39H2 function. The six affected puppies were homozygous for the variant, whereas the two non-affected littermates were heterozygous. Genotyping of a larger cohort of Greyhounds revealed that the variant is segregating in the breed and that this breed might benefit from genetic testing to avoid carrier × carrier matings.

Silencing of homeobox A5 gene in the stratum corneum of psoriasis.

Analysis of psoriatic parakeratotic cells is helpful for understanding the pathogenesis of psoriasis. Methylation analysis can be performed on psoriatic scales, but it is unclear whether genes can be silenced by DNA methylation in psoriatic stratum corneum. The present study was conducted to detect genes silenced in psoriatic stratum corneum. Methylation array analysis with 485 577 probes, quantitative real-time methylation-specific PCR (RT-MSP) and bisulphite sequencing were performed for 30 psoriatic scale samples, 6 fully developed psoriatic skin samples and 12 normal skin samples. Immunohistochemical staining of HOXA5 was performed for 29 psoriatic epidermal samples and 13 normal epidermal samples. The genome-wide methylation array detected two CpG sites within CpG islands (CGIs) located in promoter regions of HOXA5 and LIAS that had methylation levels of >0.6 in at least one of the three psoriatic scale samples and of <0.2 in all three normal skin tissue samples (methylation rate range, 0.0-1.0). RT-MSP for HOXA5CGI, in which the primers were successfully developed, revealed that the average methylation level of 27 psoriasis scales (60.2%) is significantly higher than that of 9 normal skin samples (34.6%) (P=.013). Immunohistochemical staining revealed that HOXA5 protein was not expressed in the stratum corneum of fully developed psoriatic epidermis, but the protein was expressed in the stratum corneum of incompletely developed epidermis and normal epidermis. In conclusion, HOXA5 can be silenced in the stratum corneum of psoriasis. The silenced gene was identified by non-invasive methylation analysis of psoriatic scales.

Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.

BACKGROUND: Human polyomavirus (HPyV)6 and HPyV7 are shed chronically from human skin. HPyV7, but not HPyV6, has been linked to a pruritic skin eruption of immunosuppression. OBJECTIVE: We determined whether biopsy specimens showing a characteristic pattern of dyskeratosis and parakeratosis might be associated with polyomavirus infection. METHODS: We screened biopsy specimens showing "peacock plumage" histology by polymerase chain reaction for HPyVs. Cases positive for HPyV6 or HPyV7 were then analyzed by immunohistochemistry, electron microscopy, immunofluorescence, quantitative polymerase chain reaction, and complete sequencing, including unbiased, next-generation sequencing. RESULTS: We identified 3 additional cases of HPyV6 or HPyV7 skin infections. Expression of T antigen and viral capsid was abundant in lesional skin. Dual immunofluorescence staining experiments confirmed that HPyV7 primarily infects keratinocytes. High viral loads in lesional skin compared with normal-appearing skin and the identification of intact virions by both electron microscopy and next-generation sequencing support a role for active viral infections in these skin diseases. LIMITATION: This was a small case series of archived materials. CONCLUSION: We have found that HPyV6 and HPyV7 are associated with rare, pruritic skin eruptions with a distinctive histologic pattern and describe this entity as "HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatoses."

'Hints' in the horn: diagnostic clues in the stratum corneum.

The stratum corneum or horny layer is the uppermost layer of the epidermis, and is mainly responsible for the skin's barrier function. In spite of its complexity at the ultrastructural and molecular level, the features accessible to visualization on conventional histology are relatively limited. Nevertheless, knowledge of subtle clues that one may observe in the stratum corneum can prove useful in a wide range of situations in dermatopathology. We herein review a selection of common and rare entities in which the horny layer may reveal significantly important hints for the diagnosis. These clues include parakeratosis and its different patterns (focal, confluent, alternating, associated with spongiosis, epidermal hyperplasia or lichenoid changes), subcorneal acantholysis, infectious organisms in the stratum corneum (including fungal, bacterial and parasitic), thickening or thinning of the stratum corneum and the presence of different kinds of pigment. Even when normal, the horny layer may prove to be useful when seen in association with severe epidermal damage, a combination of features testifying to the acute nature of the underlying pathological process.

Granular parakeratosis induced by benzalkonium chloride exposure from laundry rinse aids.

Benzalkonium chloride is a quaternary ammonium cationic detergent present in a number of household products, which can act as a major skin irritant. We present the case of six children who developed granular parakeratosis after exposure to benzalkonium chloride in laundry rinse aids, presenting as a brightly erythematous, tender but minimally pruritic, intertriginous eruption followed by superficial desquamation. The eruptions resolved over 3-4 weeks after cessation of exposure.

The Asian atopic dermatitis phenotype combines features of atopic dermatitis and psoriasis with increased TH17 polarization.

BACKGROUND: Atopic dermatitis (AD) shows very high prevalence in Asia, with a large unmet need for effective therapeutics. Direct comparisons between European American (EA) and Asian patients with AD are unavailable, but earlier blood studies detected increased IL-17(+)-producing cell counts in Asian patients with AD. OBJECTIVE: We sought to characterize the Asian AD skin phenotype and compare it with the EA AD skin phenotype. METHODS: We performed genomic profiling (real-time PCR) and immunohistochemistry on lesional and nonlesional biopsy specimens from 52 patients with AD (25 EAs and 27 Asians), 10 patients with psoriasis (all EAs), and 27 healthy subjects (12 EAs and 15 Asians). RESULTS: Although disease severity/SCORAD scores were similar between the AD groups (58.0 vs 56.7, P = .77), greater acanthosis, higher Ki67 counts, and frequent parakeratosis were characteristics of lesional epidermis from Asian patients with AD (P < .05). Most (24/27) Asian patients had high IgE levels. A principal component analysis using real-time PCR data clustered the Asian AD phenotype between the EA AD and psoriasis phenotypes. TH2 skewing characterized both Asian and EA patients with AD but not patients with psoriasis. Significantly higher TH17 and TH22 (IL17A, IL19, and S100A12 in lesional and IL-22 in nonlesional skin; P < .05) and lower TH1/interferon (CXCL9, CXCL10, MX1, and IFNG in nonlesional skin; P < .05) gene induction typified AD skin in Asian patients. CONCLUSION: The Asian AD phenotype presents (even in the presence of increased IgE levels) a blended phenotype between that of EA patients with AD and those with psoriasis, including increased hyperplasia, parakeratosis, higher TH17 activation, and a strong TH2 component. The relative pathogenic contributions of the TH17 and TH2 axes in creating the Asian AD phenotype need to be tested in future clinical trials with appropriate targeted therapeutics.