High Prevalence of Terbinafine Resistance Among Trichophyton mentagrophytes/T. interdigitale Species Complex, a Cross-Sectional Study from 2021 to 2022 in Northern Parts of Iran.

Treatment-resistant dermatophytosis caused by the members of the Trichophyton mentagrophytes/Trichophyton interdigitale species group (TMTISG) is increasing worldwide. We aimed to determine the prevalence of TMTISG in patients with dermatophytosis in two centers from north of Iran and detect the possible mutations in the squalene epoxidase (SQLE) gene in relevant terbinafine (TRB) resistant pathogenic isolates. From November 2021 to December 2022, 1960 patients suspected to dermatophytosis and referred to two mycology referral laboratories in the north of Iran were included in the study. Identification of all dermatophyte isolates was confirmed by RFLP of rDNA internal transcribed spacer (ITS) regions. Antifungal susceptibility testing against five common antifungals using the CLSI-M38-A3 protocol was performed. The TMTISG isolates resistant to TRB, were further analyzed to determine the possible mutations in the SQLE gene. Totally, 647 cases (33%) were positive for dermatophytosis of which 280 cases (43.3%) were identified as members of TMTISG. These were more frequently isolated from tinea corporis 131 (44.56%) and tinea cruris 116 (39.46%). Of 280 TMTISG isolates, 40 (14.3%) were resistant to TRB (MIC ≥ 4 µg/mL), all found to be T. indotineae in ITS sequencing. In SQLE sequencing 34 (85%) of TRB-resistant isolates had coincident mutations of Phe397Leu and Ala448Thr whereas four and two isolates had single mutations of Phe397Leu and Leu393Ser, respectively. Overall, the resistance of Iranian TMTISG isolates to TRB greatly occurred by a mutation of Phe397Leu in the SQLE gene as alone or in combination with Ala448Thr. Nevertheless, for the occurrence of in vitro resistance, only the presence of Phe397Leu mutation seems to be decisive.

High expression of Talin-1 is associated with tumor progression and recurrence in melanoma skin cancer patients.

BACKGROUND: Talin-1 as a component of multi-protein adhesion complexes plays a role in tumor formation and migration in various malignancies. This study investigated Talin-1 in protein levels as a potential prognosis biomarker in skin tumors. METHODS: Talin-1 was evaluated in 106 skin cancer (33 melanomas and 73 non-melanomas skin cancer (NMSC)) and 11 normal skin formalin-fixed paraffin-embedded (FFPE) tissue samples using immunohistochemical technique on tissue microarrays (TMAs). The association between the expression of Talin-1 and clinicopathological parameters, as well as survival outcomes, were assessed. RESULTS: Our findings from data minings through bioinformatics tools indicated dysregulation of Talin-1 in mRNA levels for skin cancer samples. In addition, there was a statistically significant difference in Talin-1 expression in terms of intensity of staining, percentage of positive tumor cells, and H-score in melanoma tissues compared to NMSC (P = 0.001, P < 0.001, and P < 0.001, respectively). Moreover, high cytoplasmic expression of Talin-1 was found to be associated with significantly advanced stages (P = 0.024), lymphovascular invasion (P = 0.023), and recurrence (P = 0.006) in melanoma cancer tissues. Our results on NMSC showed a statistically significant association between high intensity of staining and the poor differentiation (P = 0.044). No significant associations were observed between Talin-1 expression levels and survival outcomes of melanoma and NMSC patients. CONCLUSION: Our observations showed that higher expression of Talin1 in protein level may be significantly associated with more aggressive tumor behavior and advanced disease in patients with skin cancer. However, further studies are required to find the mechanism of action of Talin-1 in skin cancers.

Ichthyosis follicularis syndromes in patients with mutations in GJB2.

Ichthyosis follicularis (IF) manifests as generalized spiny follicular projections found in syndromic diseases secondary to SREBF1 and MBTPS2 mutations. We sought the genetic cause of IF in two distinct families from a cohort of 180 patients with ichthyosis. In Family 1, the proband (Patient 1) presented with IF, bilateral sensorineural hearing loss and punctate palmoplantar keratoderma. Using DNA from peripheral blood lymphocytes, two compound heterozygous mutations, c.526A>G and c.35delG, were discovered in GJB2. In Family 2, the proband (Patient 2) presented with a previously unreported IF phenotype in the context of keratitis-ichthyosis-deafness syndrome, and whole-exome sequencing found a de novo heterozygous mutation, c.148G>A in GJB2. Histopathology was consistent with porokeratotic eccrine ostial and dermal duct naevus (PEODDN) and IF in Patients 1 and 2, respectively. Our findings add to the clinical and histopathological spectrum of IF and emphasize the association of PEODDN-like entities with GJB2 variants.

Increasing the expression of programmed death ligand 2 (PD-L2) but not 4-1BB ligand in colorectal cancer cells.

Immune checkpoint (ICP) molecules modulate the immune response by either inducing or preventing T cell activation. Over-expression of some ICPs on malignant cells has been shown to regulate anti-tumor immune responses. We aimed to investigate the expression levels of two immune checkpoint molecules which have not been studied extensively in patients with colorectal cancer (CRC). Programmed Death Ligand 2 (co-inhibitory) and 4-1BB ligand (co-stimulatory) were assessed in tumor tissues of CRC patients compared to the adjacent normal tissues. Following tissue excision during surgical operation from 21 CRC patients, RNA extraction, cDNA synthesis and semi-quantitative real-time PCR were done for measuring the expressions of PD-L2 and 4-1BBL genes. In protein level, indirect immunohistochemistery (IHC) was performed on tissue sections. We revealed that PD-L2 was expressed in about 81% CRCs and insignificantly correlated with the tumor differentiation grade. Although a 3.25-fold change in the gene expression of PD-L2 was found in tumor tissues compared to the adjacent normal tissues (P = 0.005), but decreased level of 4-1BBL in counterpart tissues was not significant. Our results were confirmed by IHC for PDL-2 (P = 0.02) and 4-1BBL, however it was not statistically significant for the latter one. Although not significant, we could find an association between the elevated expression of PD-L2 and the tumor differentiation grade. Increased expression of negative regulator of the anti-tumor immune responses like PD-L2, as a prominent way of tumor escape, can be considered for cancer immunotherapy approaches in CRC patients using blocking monoclonal antibodies.

Diagnostic value of cytology in oral ulcer and comparison with histopathology and direct immunofluorescence.

Rapid diagnosis of pemphigus vulgaris (PV) is an important task in patient's prognosis and treatment. Although PV is routinely diagnosed through investigation of pathology specimens and direct immunofluorescence assays, Tzanck smear can be used as rapid, inexpensive, and easily used test to confirm its clinical diagnosis. This study aimed to determine the diagnostic value of Tzanck smear in erosive oral lesions of PV and also determine its sensitivity and specificity for diagnostic purposes. A total of 68 patients with erosive/ulcerated oral lesions were included in this study and divided into PV (case group) vs other causes of erosive oral lesions (control group). From all participants, two Tzanck smears were prepared for both Giemsa and hematoxylin-eosin (H&E) staining. For definite diagnosis, histopathology and direct immunofluorescence evaluations were performed based on clinical findings. The sensitivity of acantholytic cells in Tzanck smear of erosive oral lesions of PV cases was 80.5% (for both Giemsa and H&E staining), whereas specificity values of Giemsa and H&E staining were 84.6% and 96.3%, respectively. Based on our findings, the Tzanck smear of erosive oral lesions is a simple, quick, and inexpensive test for screening and primary diagnosis of PV.

Basal cell carcinoma associated with erythema ab igne.

Erythema ab igne is a skin condition mainly caused by heat exposure. Erythema ab igne usually follows a favorable prognosis. However, it may increase the risk of developing cutaneous malignancy in the involved skin. Being familiar with the type of cutaneous malignancies that may arise in the site of erythema ab igne is considerably important. To our knowledge, this letter presents the first case that shows the association between erythema ab igne and basal cell carcinoma.

A New Subtype of Lichen Planopilaris Affecting Vellus Hairs and Clinically Mimicking Androgenetic Alopecia.

BACKGROUND: Lichen planopilaris (LPP) is a follicular variant of lichen planus. A new subtype of LPP mimicking androgenetic alopecia (AGA) may be misdiagnosed. Inappropriate medical therapy or hair transplantation may exacerbate this subtype. OBJECTIVE: To introduce clinicopathologic findings of a new subtype of LPP that selectively affects vellus hair in the pattern of AGA. MATERIALS AND METHODS: In a cross-sectional study, 433 (66.6%) men and 217 (33.4%) women with alopecia who were candidates of medical treatment or hair transplantation were included. Gross and microscopic attributes of their diseases were investigated. RESULTS: Among the total of 650 patients, 58 (8.9%; 95% confidence interval, 6.7%-11.1%) patients, including 52 women and 6 men, had LPP. We identified a distinct category of LPP presenting with diffuse hair loss in the pattern of AGA with predominant terminal hair, significant decrease in vellus hair, and minute punctuate scars in histopathology. Vellus hair follicles were the main sites of involvement. Perifollicular fibrosis and mild fibrosis with lichenoid lymphocytic infiltration around infundibular area of vellus hair follicles were present. CONCLUSION: There is a new form of LPP with clinical features similar to AGA. This form is histopathologically similar to LPP but selectively affects vellus hair follicles.

Hailey-Hailey Disease: Case Series and Review of Systemic Medications.

INTRODUCTION: Hailey-Hailey disease (HHD) is a rare inherited blistering skin disorder characterized by a chronic relapsing course. While it does not pose a serious threat to the patient's health, the quality of life can change. Unfortunately, there is currently no standard treatment for this condition. OBJECTIVES: In this observational retrospective cohort study, our aim was to discover the demographic characteristics and treatment strategies for managing HHD. METHODS: In this retrospective cohort study, we documented the demographic, clinical, and histopathological characteristics beside various treatment employed options of patients diagnosed with HHD at Razi Hospital over the past 14 years. RESULTS: A total of 32 patients with HHD were enrolled in the study (15 male and 17 female). The mean age of patients was 50.41 ± 13.15 (22-77) years. The average age of disease onset was 37.31 ± 11.88 (15-60) years. Among the participants, 16 individuals (50%) affirm a positive family history of some kind of pemphigoid blisters. The most common site of disease activity was the inguinal area, observed in 14 patients (33.33%). Histopathological examination discovered the existence of suprabasal acantholysis in all of the specimens. Worthily, direct immunofluorescence analysis showed negative results in all skin biopsies. All patients received topical steroids and either topical or systemic antimicrobial agents. In cases of flares, systemic steroids were the most popular and favorable treatment choice during flares. CONCLUSION: Indeed, Hailey-Hailey disease, characterized by its chronic inflammatory and rare nature with a relapsing and remitting course, poses a significant challenge for dermatologists. The treatment of HHD has been less than satisfactory and it often presents a challenge and could be misdiagnosed. Among the available treatment options, topical steroids and antimicrobial agents are the most administered therapies.

Two asymptomatic facial erythematous macules in an adult male.

Pemphigus is a group of autoimmune bullous disorders with different types. Pemphigus foliaceous (PF) is a difficult-to-diagnosis disorder which shares clinical features with many dermatoses. We hereby, present an interesting case of PF which serves as a reminder for clinicians that pemphigus is not always a serious condition with rapid extension of lesions and it could have a very limited and benign form.

Machine learning for classification of cutaneous sebaceous neoplasms: implementing decision tree model using cytological and architectural features.

BACKGROUND: This observational study aims to describe and compare histopathological, architectural, and nuclear characteristics of sebaceous lesions and utilized these characteristics to develop a predictive classification approach using machine learning algorithms. METHODS: This cross-sectional study was conducted on Iranian patients with sebaceous tumors from two hospitals between March 2015 and March 2019. Pathology slides were reviewed by two pathologists and the architectural and cytological attributes were recorded. Multiple decision tree models were trained using 5-fold cross validation to determine the most important predictor variables and to develop a simple prediction model. RESULTS: This study assessed the characteristics of 123 sebaceous tumors. Histopathological findings, including pagetoid appearance, neurovascular invasion, atypical mitosis, extensive necrotic area, poor cell differentiation, and non-lobular tumor growth pattern, as well as nuclear features, including highly irregular nuclear contour, and large nuclear size were exclusively observed in carcinomatous tumors. Among non-carcinomatous lesions, some sebaceoma and sebaceous adenoma cases had features like high mitotic activity, which can be misleading and complicate diagnosis. Based on multiple decision tree models, the five most critical variables for lesion categorization were identified as: basaloid cell count, peripheral basaloid cell layers, tumor margin, nuclear size, and chromatin. CONCLUSIONS: This study implemented a machine learning modeling approach to help optimally categorize sebaceous lesions based on architectural and nuclear features. However, studies of larger sample sizes are needed to ensure the accuracy of our suggested predictive model.

Whole transcriptome-based skin virome profiling in typical epidermodysplasia verruciformis reveals α-, ß-, and γ-HPV infections.

HPVs are DNA viruses include approximately 450 types that are classified into 5 genera (α-, ß-, γ-, µ-, and ν-HPV). The γ- and ß-HPVs are present in low copy numbers in healthy individuals; however, in patients with an inborn error of immunity, certain species of ß-HPVs can cause epidermodysplasia verruciformis (EV), manifesting as recalcitrant cutaneous warts and skin cancer. EV presents as either typical or atypical. Manifestations of typical EV are limited to the skin and are caused by abnormal keratinocyte-intrinsic immunity to ß-HPVs due to pathogenic sequence variants in TMC6, TMC8, or CIB1. We applied a transcriptome-based computational pipeline, VirPy, to RNA extracted from normal-appearing skin and wart samples of patients with typical EV to explore the viral and human genetic determinants. In 26 patients, 9 distinct biallelic mutations were detected in TMC6, TMC8, and CIB1, 7 of which are previously unreported to our knowledge. Additionally, 20 different HPV species, including 3 α-HPVs, 16 ß-HPVs, and 1 γ-HPV, were detected, 8 of which are reported here for the first time to our knowledge in patients with EV (ß-HPV-37, -47, -80, -151, and -159; α-HPV-2 and -57; and γ-HPV-128). This study expands the TMC6, TMC8, and CIB1 sequence variant spectrum and implicates new HPV subtypes in the pathogenesis of typical EV.

Cutaneous granular cell tumor: A case series, review, and update.

Background: Granular cell tumor (GCT) or Abrikossoff's tumor is an uncommon neuro-derived tumor in which Schwann cells are found and express S-100 protein. Often, it is a benign lesion. Histopathologically, there are granular cell infiltrations through the entire dermis without necrosis which are periodic acid Schiff (PAS) stain positive and reactive with S-100. The aim of this study is the clinicopathological evaluation of GCT. Material and Methods: In this paper, we described the experience of 6 patients with a GCT in different locations (4 cases in the skin and 2 cases in the mucosa), for example, a case with a tumor in the abdomen and a keloidal-like presentation with a highly sclerotic pattern (an uncommon pathological feature). Another case developed a lesion secondary to physical trauma. Result: In one case, the presence of a lesion in the lower lip associated with actinic damage secondary to chronic sun exposure resulted in misdiagnosis with actinic cheilitis and squamous cell carcinoma. Conclusion: Histopathologically, there were granular cell infiltrations through the entire dermis without necrosis which are PAS-positive and reactive with S-100.

Dipeptidyl-Peptidase 4 Inhibitor-Induced Variants of Bullous Pemphigoid: A Case Series of Four Patients.

Bullous pemphigoid is the most common acquired bullous disease with an autoimmune basis and a tendency to involve mostly old people. By rising incidence of diabetes all over the world, consumption of antidiabetes medications has also increased. One of the most used antidiabetes drugs is gliptin family (dipeptidyl-peptidase 4 inhibitor). Recently, this class of oral antidiabetic agents showed a correlation with the occurrence of bullous pemphigoid and its subtypes, including mucous membrane pemphigoid and pemphigoid nodularis. We are reporting a case series of 4 diabetes patients that we diagnosed with bullous pemphigoid subtypes (mucous membrane pemphigoid, pemphigoid nodularis, and its rarest subtype, linear IgA bullous dermatosis) after taking different drugs of gliptin family.

Coexistence of Pemphigus Vulgaris and Lichen Planus following COVID-19 Vaccination.

SARS-CoV-2 vaccines were approved without long-term monitoring due to emergent situation and might have several side effects. Herein, we describe the first case with development of both LP and PV following COVID-19 vaccination. Immunological alteration due to COVID-19 vaccination and its potential role in triggering autoimmune disorders were also dealt with.

Remission of Prurigo Pigmentosa after Breaking Ketogenic Diet and Resuming Regular Diet.

Prurigo pigmentosa (PP) is a rare skin disorder presenting as erythematous urticarial papules on the chest and leaving reticulated pigmentation. Although the etiology of PP is unknown, conditions associated with ketosis such as diabetes mellitus, ketogenic diet (KD), and anorexia nervosa are implicated. Herein, we report a 21-year-old woman who developed PP after adhering to a KD and responded to resuming a regular diet.

Oral and jaw lymphoma in an Iranian population.

INTRODUCTION: Lymphoma is the second most common malignancy of head and neck. Many studies have been carried out in different population groups to detect the subtypes of oral and jaw lymphoma, but such research has not been conducted in Iran. The purpose of this study was to determine the subtypes of oral and jaw lymphoma by immunohistochemistry. MATERIALS AND METHODS: A total of 36 paraffin-embedded blocks (25 males and 11 females) with primary diagnosis of non-Hodgkin lymphoma were studied by immunohistochemical markers according to cellular morphology. RESULTS: The frequencies were diffuse large B-cell (41.1%), low-grade B-cell (35.2%), peripheral T-cell (11.7%), Burkitt (5.8%), and Hodgkin lymphomas (5.8%). The involved sites were salivary gland (26.4%), maxillary bone (23.5%), mandibular soft tissues (17.6%), maxillary sinus (14.7%), mandibular bone (8.8%), tonsils and tongue (5.7%), and lip and vestibule (2.9%), and 2 cases (5.5%) turned out to be undifferentiated carcinomas. The most common lymphomas in male and females were diffuse large B-cell and low-grade B-cell lymphomas, respectively. CONCLUSIONS: The epidemiology of different types of oral lymphoma in a sample of Iranian population was not similar with other populations of the world. Immunohistochemistry and molecular methods are required to prove the diagnosis in addition to typing of lymphoma.

Prevalence and Main Determinants of BRAF V600E Mutation in Dysplastic and Congenital Nevi.

BACKGROUND & OBJECTIVE: Predicting the transformation of dysplastic or congenital nevi into malignant lesions results in a significant increase in the survival of patients. Some specific gene mutations have been reported to be very helpful in this regard. Therefore, this study aimed to evaluate the prevalence of BRAF V600E mutation in dysplastic and congenital nevi. METHODS: This cross-sectional study was conducted on patients with congenital (n=30) or dysplastic (n=30) nevi. For genomic analysis, the BRAF gene mutation (V600E) was evaluated using the real-time polymerase chain reaction. RESULTS: The prevalence of BRAF gene (V600E) mutation was found as 1 case (3.3%) in congenital and 8 cases (26.7%) in dysplastic nevi indicating the higher prevalence of this mutation in patients with dysplastic nevi (P=0.026). Moreover, in the dysplastic nevi group, the presence of BRAF gene mutation (V600E) showed a significant relationship with the severity of dysplasia as the mutation rate was 25% in mild cases, in comparison with 54.5% in moderate dysplasia cases (P=0.009). CONCLUSION: According to the results, 3.3% of the patients with congenital nevi and 26.7% of the subjects with dysplastic nevi were positive for BRAF V600E mutation. Furthermore, the severity of dysplasia could have a positive relationship with the presence of the mutation.

Coexistence of Neonatal Lupus Erythematous and Sturge-Weber Syndrome.

Neonatal lupus erythematous (NLE) is a rare condition presented by lupus dermatitis shortly after birth or later following sun exposure. Sturge-Weber syndrome (SWS) is also an uncommon congenital condition characterized by extensive capillary malformation and ophthalmic and/or neurologic involvement. Here, we describe the first case of coexistence of NLE and SWS which posed a significant diagnostic challenge to clinicians.