Pilomatrixomas: 31 years of experience in population under and over 18 years of age.

BACKGROUND: Pilomatrixoma, also known as calcifying epithelioma of Malherbe, is a benign cutaneous neoplasm that demonstrates differentiation towards the matrix portion of hair follicles. It is the most common benign cutaneous neoplasm in childhood and youth, although it can occur at any age. With a general incidence ranging from 0.001% to 0.0031% of all cutaneous tumors. There is a slight predilection for females, with a female-to-male ratio of 1.15:1. METHODS: Observational, descriptive, retrospective, and cross-sectional study conducted using the electronic database of the dermatopathology department of Dr. Manuel Gea González General Hospital, from January 1992 to July 2023. Only cases with a histopathological diagnosis of pilomatrixoma, pilomatricoma, and Malherbe's calcifying epithelioma were included. RESULTS: A total of 200 pilomatrixomas were recorded in 177 patients. The tumor predominantly affected females in the pediatric age group, with an average age of 22.98 years in the studied population. The most common location was the head (periorbital region), followed by the upper extremities and trunk. Upon separating the population into pediatric and adult groups, 111 and 89 cases were identified, respectively. CONCLUSIONS: We present a detailed study on pilomatrixomas with a comprehensive overview of the demographic, clinical, and epidemiological characteristics of this benign cutaneous neoplasm. The results revealed robust statistical data highlighting the distribution by age, gender, topography, morphology, accompanying symptoms, and frequency of clinical differential diagnoses. This study significantly contributes to the existing knowledge of pilomatrixomas and serves as a valuable reference for future research and clinical practice.

INTRODUCCIÓN: El pilomatrixoma o epitelioma calcificado de Malherbe es una neoplasia cutánea benigna que muestra diferenciación hacia la porción de la matriz de los folículos pilosos. Es la neoplasia cutánea benigna más frecuente en la infancia y la juventud, aunque puede ocurrir a cualquier edad. Tiene una incidencia general que oscila entre el 0.001% y el 0.0031% de todos los tumores cutáneos. Se reporta una ligera predilección por el sexo femenino, con una relación mujer: hombre de 1.15:1. MÉTODOS: Estudio observacional, descriptivo, retrospectivo y transversal en el que se utilizó la base de datos electrónica del departamento de dermatopatología del Hospital General Dr. Manuel Gea González, entre enero de 1992 y julio de 2023. Para la búsqueda de los casos solo se incluyeron aquellos con diagnóstico histopatológico de pilomatrixoma, pilomatricoma o epitelioma calcificado de Malherbe. RESULTADOS: Se registraron 200 pilomatrixomas en 177 pacientes. El tumor predominó en mujeres de edad pediátrica; el promedio de edad de la población estudiada fue 22.98 años. La topografía más frecuente fue la cabeza (región periorbitaria), seguida de las extremidades superiores y el tronco. Al separar la población en pediátricos y adultos, se encontraron 111 y 89 casos, respectivamente. CONCLUSIONES: Presentamos un estudio detallado sobre pilomatrixomas con una visión exhaustiva de las características demográficas, clínicas y epidemiológicas de esta neoplasia cutánea benigna. Los resultados revelaron datos estadísticos sólidos, destacando la distribución por edades, sexo, topografía, morfología, síntomas acompañantes y frecuencia de diagnósticos diferenciales clínicos. Este estudio contribuye significativamente al conocimiento existente sobre los pilomatrixomas y sirve como una referencia valiosa para futuras investigaciones y para la práctica clínica.

Epidermal growth factor receptor inhibition leads to cellular phenotype correction of DSP-mutated keratinocytes.

Desmoplakin (DSP) is a desmosomal component expressed in skin and heart, essential for desmosome stability and intermediate filament connection. Pathogenic variants in the DSP gene encoding DSP, lead to heterogeneous skin, adnexa and heart-related phenotypes, including skin fragility, woolly hair (WH), palmoplantar keratoderma (PPK) and arrhythmogenic/dilated cardiomyopathy (ACM/DCM). The ambiguity of computer-based prediction analysis of pathogenicity and effect of DSP variants, indicates a necessity for functional analysis. Here, we report a heterozygous DSP variant that was not previously described, NM_004415.4:c.3337C>T (NM_004415.4(NP_004406.2):p.(Arg1113*)) in a patient with PPK, WH and ACM. RNA and protein analysis revealed ~50% reduction of DSP mRNA and protein expression. Patient's keratinocytes showed fragile cell-cell connections and perinuclear retracted intermediate filaments. Epidermal growth factor receptor (EGFR) is a transmembrane protein expressed in the basal epidermal layer involved in proliferation and differentiation, processes that are disrupted in the development of PPK, and in the regulation of the desmosome. In skin of the abovementioned patient, evident EGFR upregulation was observed. EGFR inhibition in patient's keratinocytes strongly increased DSP expression at the plasma membrane, improved intermediate filament connection with the membrane edges and reduced the cell-cell fragility. This cell phenotypic recovery was due to a translocation of DSP to the plasma membrane together with an increased number of desmosomes. These results indicate a therapeutic potential of EGFR inhibitors for disorders caused by DSP haploinsufficiency.

Androgen Receptor Immunohistochemistry is Superior to PRAME for the Differentiation of Sebaceous Carcinoma From Primary Cutaneous Basaloid Mimics.

ABSTRACT: Cutaneous sebaceous neoplasia comprises a spectrum of disease ranging from benign adenomas to malignant carcinomas. The hallmark of these lesions is sebaceous differentiation. However, poorly-differentiated sebaceous carcinoma (SC), which lacks significant overt sebaceous differentiation, can show morphologic overlap with a variety of other basaloid cutaneous neoplasms. The accurate classification of SC is essential not only for diagnosis, but also because of the potential association with Muir-Torre syndrome. Androgen receptor (AR) is a sensitive, but not entirely specific immunohistochemical marker that has been used for the diagnosis of SC. PReferentially expressed Antigen in MElanoma (PRAME) demonstrates strong cytoplasmic labeling of mature sebocytes and has been reported to be expressed in a variety of sebaceous neoplasms, including in the basaloid cell component. Therefore, we sought to compare the diagnostic use of cytoplasmic PRAME expression with that of AR for the distinction of SC from a cohort of basaloid cutaneous mimics; namely basal cell carcinoma, basaloid squamous cell carcinoma, pilomatricoma, cutaneous lymphadenoma, and extra-mammary Paget disease. We report that cytoplasmic PRAME expression is uncommon in poorly differentiated SC, and although specific, it shows very low sensitivity (22%). In contrast, AR was moderately sensitive (66%) and highly specific (92%) for the distinction of SC from basaloid mimics. These attributes, in addition to the nuclear expression of AR in the sebocytic and basaloid components of SC, suggest that AR is superior to PRAME for the diagnosis of SC.

Gut microbiota and polycystic ovary syndrome, focus on genetic associations: a bidirectional Mendelian randomization study.

Background: The contribution of gut microbiota to the pathogenesis of polycystic ovary syndrome (PCOS) is controversial. The causal relationship to this question is worth an in-depth comprehensive of known single nucleotide polymorphisms associated with gut microbiota. Methods: We conducted bidirectional Mendelian randomization (MR) utilizing instrumental variables associated with gut microbiota (N = 18,340) from MiBioGen GWAS to assess their impact on PCOS risk in the FinnGen GWAS (27,943 PCOS cases and 162,936 controls). Two-sample MR using inverse variance weighting (IVW) was undertaken, followed by the weighted median, weighted mode, and MR-Egger regression. In a subsample, we replicated our findings using the meta-analysis PCOS consortium (10,074 cases and 103,164 controls) from European ancestry. Results: IVWMR results suggested that six gut microbiota were causally associated with PCOS features. After adjusting BMI, SHBG, fasting insulin, testosterone, and alcohol intake frequency, the effect sizes were significantly reduced. Reverse MR analysis revealed that the effects of PCOS features on 13 gut microbiota no longer remained significant after sensitivity analysis and Bonferroni corrections. MR replication analysis was consistent and the results suggest that gut microbiota was likely not an independent cause of PCOS. Conclusion: Our findings did not support the causal relationships between the gut microbiota and PCOS features at the genetic level. More comprehensive genome-wide association studies of the gut microbiota and PCOS are warranted to confirm their genetic relationship. Declaration: This study contains 3533 words, 0 tables, and six figures in the text as well as night supplementary files and 0 supplementary figures in the Supplementary material.

Clinicopathological and immunohistochemical characteristics of bullous pilomatricoma: a retrospective, single-center study, and comparison with ordinary pilomatricoma.

BACKGROUND: Bullous pilomatricoma is a rare variant of pilomatricoma. As it has been published in sporadic case reports, a limited understanding of its clinicopathological characteristics restricts its effective diagnosis and treatment. OBJECTIVES: This study aimed to analyze the clinicopathological and immunohistochemical characteristics of bullous pilomatricoma to better understand the bullous transformation of pilomatricoma. METHODS: The authors conducted a retrospective study of 12 patients with bullous pilomatricoma and compared their clinical, histopathological, and immunohistochemical data with those of patients with ordinary pilomatricoma. RESULTS: Bullous pilomatricoma showed no sex preference, with a mean onset age of 31.2 years. The common sites were the upper extremities and trunk. Bullous pilomatricoma had a shorter disease duration, a larger diameter, and a greater tendency to increase in size than those of ordinary pilomatricoma. Histopathologically, bullous pilomatricoma had a shorter duration, lesser calcification, more mitotic figures, and distinct dermal features from those of ordinary pilomatricoma. Immunohistochemically, the expression of Matrix Metalloprotease (MMP)-2, MMP-9, vascular endothelial growth factor receptor-3 (VEGFR-3), and VEGF-C was elevated. STUDY LIMITATIONS: The study was retrospective, and the sample size was small. CONCLUSION: The distinctive features of bullous pilomatricoma potentially result from dermal changes associated with the release of angiogenic factors and proteolytic enzymes. This comprehensive analysis provides novel insights into the clinical features and pathogenesis of bullous pilomatricoma.

Evaluation of Surface Structure and Morphological Phenomena of Caucasian Virgin Hair with Atomic Force Microscopy.

Background and Objectives: Atomic force microscopy (AFM) as a type of scanning microscopy (SPM), which has a resolution of fractions of a nanometer on the atomic scale, is widely used in materials science. To date, research using AFM in medicine has focused on neurodegenerative diseases, osteoporosis, cancer tumors, cell receptors, proteins and the DNA mismatch repair (MMR) system. Only a few small studies of hair imaging have been conducted, mostly in biotechnology or cosmetology. Thanks to the possibilities offered by AFM imaging, dermatologists can non-invasively assess the condition of hair and its possible disorders. Our goal was to capture images and microscopically analyze morphological changes in the surface of healthy hair. Materials and Methods: In this study, three to five hairs were collected from each person. Each hair was examined at nine locations (0.5; 1.0; 1.5; 2.0; 3.5; 4.5; 5.5; 6.5 and 7.0 cm from the root). At least 4 images (4-10 images) were taken at each of the 9 locations. A total of 496 photos were taken and analyzed. Metric measurements of hair scales, such as apparent length, width and scale step height, were taken. Results: This publication presents the changes occurring in hair during the natural delamination process. In addition, morphoological changes visualized on the surface of healthy hair (pitting, oval indentations, rod-shaped macro-fibrillar elements, globules, scratches, wavy edge) are presented. A quantitative analysis of the structures found was carried out. Conclusions: The findings of this study can be used in further research and work related to the subject of human hair. They can serve as a reference for research on scalp and hair diseases, as well as hair care.

Tumor of follicular infundibulum - reappraisal in a series of 28 patients with critical review of the literature.

BACKGROUND AND OBJECTIVES: Tumor of follicular infundibulum (TFI) has been described as a neoplasm - isolated and multiple - and in association with other lesions. Its histopathologic definition is controversial. PATIENTS AND METHODS: We present a histopathologically analyzed series of 28 patients with TFI features. This has been supplemented by a search in MEDLINE on the literature on this subject. The corresponding figures given in these articles have been discussed and analyzed. RESULTS: Patients comprised 16 women and twelve men. TFI features were seen in five patients with nevus sebaceous, two trichofolliculomas, one dilated pore Winer, eight viral warts, one dermatofibroma, six seborrheic keratoses, three actinic keratoses, one invasive squamous cell carcinoma, and one basal cell carcinoma in association with a squamous cell carcinoma/actinic keratosis. After study of the literature especially of solitary cases of TFI, we interpret such cases mostly as variants of seborrheic keratoses with variable degree of infundibular, isthmic and/or sebaceous differentiation with or without regression. CONCLUSIONS: We regard TFI as an epithelial growth pattern which may occur in hamartomatous, inflammatory, infectious, reactive, or neoplastic conditions, in most solitary forms likely best classified within the histopathological spectrum of seborrheic keratoses.

TRPS1 modulates chromatin accessibility to regulate estrogen receptor alpha (ER) binding and ER target gene expression in luminal breast cancer cells.

Common genetic variants in the repressive GATA-family transcription factor (TF) TRPS1 locus are associated with breast cancer risk, and luminal breast cancer cell lines are particularly sensitive to TRPS1 knockout. We introduced an inducible degron tag into the native TRPS1 locus within a luminal breast cancer cell line to identify the direct targets of TRPS1 and determine how TRPS1 mechanistically regulates gene expression. We acutely deplete over 80 percent of TRPS1 from chromatin within 30 minutes of inducing degradation. We find that TRPS1 regulates transcription of hundreds of genes, including those related to estrogen signaling. TRPS1 directly regulates chromatin structure, which causes estrogen receptor alpha (ER) to redistribute in the genome. ER redistribution leads to both repression and activation of dozens of ER target genes. Downstream from these primary effects, TRPS1 depletion represses cell cycle-related gene sets and reduces cell doubling rate. Finally, we show that high TRPS1 activity, calculated using a gene expression signature defined by primary TRPS1-regulated genes, is associated with worse breast cancer patient prognosis. Taken together, these data suggest a model in which TRPS1 modulates the genomic distribution of ER, both activating and repressing transcription of genes related to cancer cell fitness.

Use of Multiple Machine Learning Approaches for Selecting Urothelial Cancer-Specific DNA Methylation Biomarkers in Urine.

Diagnosing urothelial cancer (UCa) via invasive cystoscopy is painful, specifically in men, and can cause infection and bleeding. Because the UCa risk is higher for male patients, urinary non-invasive UCa biomarkers are highly desired to stratify men for invasive cystoscopy. We previously identified multiple DNA methylation sites in urine samples that detect UCa with a high sensitivity and specificity in men. Here, we identified the most relevant markers by employing multiple statistical approaches and machine learning (random forest, boosted trees, LASSO) using a dataset of 251 male UCa patients and 111 controls. Three CpG sites located in ALOX5, TRPS1 and an intergenic region on chromosome 16 have been concordantly selected by all approaches, and their combination in a single decision matrix for clinical use was tested based on their respective thresholds of the individual CpGs. The combination of ALOX5 and TRPS1 yielded the best overall sensitivity (61%) at a pre-set specificity of 95%. This combination exceeded both the diagnostic performance of the most sensitive bioinformatic approach and that of the best single CpG. In summary, we showed that overlap analysis of multiple statistical approaches identifies the most reliable biomarkers for UCa in a male collective. The results may assist in stratifying men for cystoscopy.

A Comparative Evaluation of TRPS1 and GATA3 in adenoid cystic, secretory, and acinic cell carcinomas of the breast and salivary gland.

GATA3 is the most used marker to determine tumors' breast origin, but its diagnostic value in triple-negative breast cancer (TNBC) is limited. The newly identified TRPS1 is highly sensitive and specific for breast carcinoma, especially TNBC. Here, we compared the utility of TRPS1 and GATA3 expression in a subset of salivary gland-type breast tumors (including adenoid cystic, acinic cell, and secretory carcinomas [AdCC, ACC, and SC, respectively]), and we compared TRPS1 and GATA3 expression of such tumors with head and neck (H&N) and AdCC of upper respiratory tumors. TRPS1 was strongly expressed in basaloid TNBC and AdCCs with solid components, including 100 % of mixed and solid breast AdCCs. However, TRPS1 was positive in only 50 % cribriform AdCCs. Expression patterns of TRPS1 in H&N and upper respiratory AdCC were similar. TRPS1 was positive in 30 % of H&N cribriform AdCCs but was strongly expressed in mixed AdCC (67 %) and solid AdCC (100 %). In the upper respiratory AdCCs, TRPS1 was positive in 58.4 % of cribriform AdCCs and positive in 100 % of AdCCs with solid components. On the contrary, GATA3 was negative in predominant AdCCs of the breast, H&N, and upper respiratory tract. These data show that GATA3 and TRPS1 expression varies AdCCs. In addition, TRPS1 and GATA3 expression patterns were similar SC and ACC of breast and H&N. Both markers were positive in SC and negative in ACC. Therefore, TRPS1 and GATA3 cannot be used to differentiate salivary gland-type carcinomas of breast origin from those of upper respiratory or H&N origin.

Disruption of TUFT1, a Desmosome-Associated Protein, Causes Skin Fragility, Woolly Hair, and Palmoplantar Keratoderma.

Desmosomes are dynamic complex protein structures involved in cellular adhesion. Disruption of these structures by loss-of-function variants in desmosomal genes leads to a variety of skin- and heart-related phenotypes. In this study, we report TUFT1 as a desmosome-associated protein, implicated in epidermal integrity. In two siblings with mild skin fragility, woolly hair, and mild palmoplantar keratoderma but without a cardiac phenotype, we identified a homozygous splice-site variant in the TUFT1 gene, leading to aberrant mRNA splicing and loss of TUFT1 protein. Patients' skin and keratinocytes showed acantholysis, perinuclear retraction of intermediate filaments, and reduced mechanical stress resistance. Immunolabeling and transfection studies showed that TUFT1 is positioned within the desmosome and that its location is dependent on the presence of the desmoplakin carboxy-terminal tail. A Tuft1-knockout mouse model mimicked the patients' phenotypes. Altogether, this study reveals TUFT1 as a desmosome-associated protein, whose absence causes skin fragility, woolly hair, and palmoplantar keratoderma.

What is in a name-Perifollicular fibroma or fibrofolliculoma?

So far, confusion exists regarding the question of whether hereditary perifollicular fibromas and fibrofolliculomas can be distinguished from each other. Here, histopathological arguments are presented to clarify this terminological problem. In 1977, Birt et al. described a large kindred affected with hereditary multiple "fibrofolliculomas," which they thought were "a hitherto unrecognized pilar hamartoma," but they never claimed the fibrofolliculomas were part of a syndrome. A careful microscopic comparison shows, however, that the tumors are clinically and histopathologically identical to perifollicular fibromas, as first described by Burnier and Rejsek in 1925. Their familial occurrence was discovered in 1971 by Civatte and Le Tréguilly. Before 1977, the term "perifollicular fibroma" was used for these skin tumors. By contrast, Hornstein and Knickenberg described in 1975 perifollicular fibromas as a cutaneous marker of a syndrome characterized by a predisposition to colon cancer and pneumothorax. Later, two French groups erroneously proposed the term "Birt-Hogg-Dubé syndrome" to describe the co-occurrence of fibrofolliculomas, trichodiscomas, and acrochordons, which was contrary to what Birt et al. had in mind. Hence, today, we should discriminate between the hereditary nonsyndromic perifollicular fibromas, as documented by Civatte and Le Tréguilly and later by Birt et al., and the syndromic perifollicular fibromas, as delineated by Hornstein and Knickenberg.

Cochlear implantation in Bjornstad syndrome: a case series with literature review.

BACKGROUND: To report the presentation, diagnostic process, management and results of cochlear implantation of patients diagnosed with Bjornstad syndrome with profound sensorineural hearing loss (SNHL). CASE PRESENTATION AND MANAGEMENT: A retrospective report of two siblings with Bjornstad syndrome suffering profound SNHL unresponsive to conventional hearing aids treated with bilateral simultaneous cochlear implantation. SETTING: Tertiary-referral center. RESULTS: Cochlear implant surgeries of two siblings (four ears) with profound SNHL and bilateral inner ear anomaly (incomplete partition type 1) were performed without complications. Postoperative audiometric measurements showed a significiant improvement in pure-tone threshold and a word recognition score. In the literature review, no previous case of Bjornstad syndrome treated with cochlear implantation has been reported. CONCLUSIONS: Cochlear implantation is an effective, safe, and ultimate treatment option for Bjornstad syndrome with profound SNHL not responding to hearing aids.

Epidemiology, clinical characteristics, treatment, and outcomes of proliferating pilar tumors: A systematic review.

BACKGROUND: Proliferating pilar tumors (PPTs) are rare cutaneous neoplasms arising from hair follicles that have both malignant and metastatic potential. OBJECTIVE: To present a systematic review of the epidemiology, clinical characteristics, and treatment and outcome data on PPTs. METHODS: Using the OVID platform, MEDLINE and Embase were searched from inception until May 26, 2022. All studies that provided original data on PPTs in English were included. References of these studies were also cross-checked to identify any additional relevant articles. Oxford's Levels of Evidence-Based Medicine was used for quality assessment. RESULTS: A total of 114 articles, providing data on 361 cases of PPTs, were included in our synthesis. Every study included was either a case series or case report. The mean age at diagnosis was 61.7. Most patients in the synthesis were female (71%), and the majority of cases occurred on the scalp (73.1%). The presence or absence of cytological atypia was only reported in one-third of the cases; 36.8% of cases were classified as malignant and 7.5% metastasized. Although no lesions treated with Mohs micrographic surgery required adjuvant radiation and only one reported recurrence occurred after Mohs surgery, there is insufficient data to make conclusions on a superior treatment modality. LIMITATIONS: All studies in this review were either case reports or case series. CONCLUSIONS AND RELEVANCE: Our study supports the notion that PPTs occur most commonly on the scalp of elderly female patients. Moreover, our findings confirm that PPT is capable of demonstrating aggressive biology and metastasis. Given the lack of uniformity in histologic description, pathologists should be encouraged to comment on the presence and degree of cytological atypia when reporting cases of rare neoplasms such as the PPT. Greater consensus on diagnosis and classification as well as more robust data is needed regarding optimal management.