Study on the correlation of high expression level of HuD with seborrheic keratosis and skin aging.

BACKGROUND: Currently, most studies of ELAV (Embryonic Lethal, Abnormal Vision, Drosophila)-like protein 4 (Hu antigen D, HuD) focus on nervous system-related diseases; the role of HuD in the occurrence of skin aging and seborrheic keratosis (SK) has not been reported. OBJECTIVE: To explore the role of HuD in the occurrence of SK and skin aging and its related clinical significance. METHODS: The expression levels of HuD in the skin and blood of healthy people at different ages, SK lesions, and perilesional skin of SK patients were detected by both immunohistochemistry and Western blotting. The mRNA expression levels of HuD in the skin and blood of healthy peoples at different ages were detected by quantitative real-time reverse transcription-polymerase chain reaction. The expression level of HuD was compared with the skin of healthy people, SK lesion, and perilesional skin of SK patients of the same age. RESULTS: The immunohistochemistry and Western blotting showed that the expression levels of HuD in SK lesions were higher than those in healthy skin and perilesional skin. The immunohistochemical staining intensity, protein and mRNA expression levels of HuD in the skin and blood of healthy people were correlated with age, which gradually increased with increasing age. CONCLUSION: HuD is highly expressed in SK lesion and aged skin, indicating that a higher HuD expression level is correlated with occurrence of SK and aging skin; however, its mechanism needs to be further studied.

Upregulated Guanine Deaminase Is Involved in Hyperpigmentation of Seborrheic Keratosis via Uric Acid Release.

Seborrheic keratosis, which is a benign tumor composed of epidermal keratinocytes, develops common in the elderly. Uric acid generated by upregulated guanine deaminase (GDA) has been identified to cause UV-induced keratinocyte senescence in seborrheic keratosis. Seborrheic keratosis is also frequently pigmented. Growing evidences indicate that hyperuricemia is a risk factor of acanthosis nigricans, an acquired skin hyperpigmentation. The objective of this study was to investigate role of GDA and its metabolic end product, uric acid, in hyperpigmentation of patients with seborrheic keratosis using their lesional and non-lesional skin specimen sets and cultured primary human epidermal keratinocytes with or without GDA overexpression or uric acid treatment. GDA-overexpressing keratinocytes or their conditioned media containing uric acid increased expression levels of MITF and tyrosinase in melanocytes. Uric acid released from keratinocytes was facilitated by ABCG2 transporter with the help of PDZK1 interaction. Released uric acid was taken by URAT1 transporter in melanocytes, stimulating melanogenesis through p38 MAPK activation. Overall, GDA upregulation in seborrheic keratosis plays a role in melanogenesis via its metabolic end product uric acid, suggesting that seborrheic keratosis as an example of hyperpigmentation associated with photoaging.

Overexpression of Amyloid Precursor Protein Promotes the Onset of Seborrhoeic Keratosis and is Related to Skin Ageing.

Seborrhoeic keratosis (SK) is an age-related skin disease. Amyloid precursor protein (APP) plays an important role in the pathogenesis of age-related Alzheimer's disease. The aim of this study was to elucidate the expression characteristics of APP in SK tissues (n = 50), and explore whether the production of APP is related to the onset of SK and skin ageing, including ultraviolet (UV)-induced ageing, as observed in normal skin (n = 79). The results of immunohistochemistry, Western blotting and quantitative real-time PCR showed that APP and its downstream products (i.e. amyloid-ß42) were more highly expressed in SK than in paired adjacent normal skin tissues. In contrast, the expression of its key secretase (i.e. ß-secretase1) was generally low. Furthermore, APP expression was higher in UV-exposed than non-exposed skin sites, and expression in the older age group (61-85 years) was greater than that in the younger age group (41-60 years) in SK tissues (p<0.05). APP expression correlated positively with age in epidermis (p<0.05), but not in dermis. These findings suggest that overexpression of APP may promote the onset of SK and is a marker of skin ageing and UV damage. Further research will elucidate whether therapeutic mitigation of increased levels of APP in the skin might delay the onset of SK and skin ageing.

Two cases of seborrheic keratosis of the external ear canal: involvement of PIK3CA and FGFR3 genes.

BACKGROUND: Seborrheic keratosis (SK) of the outer ear canal is rarely described in literature. Etiological risk factors involved in SK such as exposure to human papillomavirus (HPV) and ultraviolet (UV) light are established but must still be confirmed. In recent years, new insights into the pathogenesis of SKs occurred in the area of molecular pathogenesis. Fibroblast growth factor receptor 3 (FGFR3) gene and p110α subunit of phosphoinositide 3-kinase (PIK3CA) oncogene mutations are known to be involved. METHODS: We describe two cases of SK of the outer ear canal. We conducted a review of literature and examined the role of etiological risk factors involved in our cases. The lesions were primarily treated with surgical resection. Postoperatively, in both patients, the lesions recurred after a considerably long disease-free interval. We tested both FGFR3 and PIK3CA genes for mutations, in the primary and recurrent lesions. RESULTS: We did not find any mutations in both genes in all samples. CONCLUSION: Additional research is needed to further establish possible etiological risk factors and to clarify the involvement of PIK3CA and FGFR3 genes in the pathogenesis of seborrheic keratosis of the outer ear canal. These cases underscore the need for meticulous diagnosis, treatment, and sufficient long-term follow-up.

Differential Diagnosis of Seborrheic Keratosis: Clinical and Dermoscopic Features.

Seborrheic keratosis (SK) is a benign epidermal keratinocytic tumor that is extremely common, particularly in individuals over the age of 50. Most individuals with SK will have more than one lesion and the presence of over 10 lesions in the same person is not uncommon. Although the clinical morphology of most SK with their stuck-on, symmetric, keratotic, and waxy appearance makes them easy to identify, many manifest a morphology resembling melanoma or squamous cell carcinoma. One can argue that such cases will ultimately not prove to be problematic since a simple biopsy will easily reveal their benign nature and eliminate any concerns. However, the cost and morbidity associated with the biopsy of benign lesions should not be underestimated. Methods to improve our in vivo ability to correctly identify SK will prove beneficial not only to the health care system in general but to the individual patient specifically. The issue of greater concern resides with skin cancers that mimic SK or when skin cancers arise in association with SK. Needless to say, in vivo methods to help identify malignancy and differentiate them from benign lesions would be welcomed by all. Fortunately, we do now have in vivo imaging methods such as dermoscopy that can improve the clinician's diagnostic accuracy. In this article, we summarize the current knowledge regarding the clinical and dermoscopic features of SK, and provide clues to aid in their diagnosis.

J Drugs Dermatol. 2017;16(9):835-842.

[Expression of epidermal growth factor receptor in patients with insulin resistance and seborrheic keratomas]. / Ékspressiia retseptora épidermal'nogo faktora rosta pri nalichii insulinorezistentnosti u patsientov s seboreinymi keratomami.

AIM: to study the expression of epidermal growth factor receptor (EGFR) in patients with seborrheic keratomas (SK) and insulin resistance (type 2 diabetes mellitus (DM2)) and in those without concomitant carbohydrate metabolic disturbances. SUBJECTS AND METHODS: 80 patients with SK were examined. According to the presence or absence of DM2, the patients were divided into 2 groups: 1) 40 patients with concomitant DM2; 2) 40 people without carbohydrate metabolic disturbances. DM2 was diagnosed on the basis of laboratory studies and an endocrinologist's consultation. Histological and immunohistochemical (IHC) examinations using anti-EGFR antibodies were performed; two intact skin sections from the patients with DM2 and two intact skin sections from those without carbohydrate metabolic disturbances were used as a control. RESULTS: The ICH examination using anti-EGFR monoclonal antibodies revealed that Group 1 showed intense diffuse membrane staining of more than 50% of the cells in 32 (80%) patients, moderate (30-50% cells) and weak (10-30% cells) staining in 6 (15%) and 2 (5%) patients, respectively. Marked EGFR expression was also noted in two intact skin biopsy specimens taken from patients with DM2. In Group 2, the staining intensity was weak in more than 10% but less than 30% of the SK cells in 28 (70%) patients; moderate EGFR expression was observed in 9 (22.5%) and diffuse, pronounced, staining in more than 50% of the SK cells was in 3 (7.5%) patients. The intact skin biopsy specimens taken from 2 patients without carbohydrate metabolic disturbances displayed a weak EGFR expression in the basal cell layer of the epidermis. CONCLUSION: EGFR overexpression in SK may be a result of metabolic disorders rather than a diagnostic sign of malignant neoplasms of the internal organs. The increased EGFR expression revealed in patients with SK and concomitant DM2 is caused by insulin resistance and hyperinsulinemia, in which the dysregulation of insulin signal transmission into the cell leads to changes in EGF synthesis and signaling pathway that regulates cell proliferation and growth.

Familial seborrhoeic keratosis associated with multiple 'pure reticulated acanthomas' and infundibulocystic basal cell carcinomas.

BACKGROUND: A variety of genodermatoses with multiple cutaneous tumours and germline genetic alterations, such as PTCH1 mutations, have been described. Other cutaneous syndromes have been associated with somatic gene mutations, such as FGFR3 in familial seborrhoeic keratosis. OBJECTIVES: To describe the clinical, dermoscopic and histopathological features of multiple cutaneous lesions, mostly infundibulocystic basal cell carcinomas (ICBCCs) and pure reticulated acanthomas, present in a family affected by familial seborrhoeic keratosis. In addition, we tested for possible germline alterations in FGFR3 and PTCH1. METHODS: Ten members of one family were clinically examined and 92 skin biopsy specimens were evaluated. Blood samples from six individuals were analysed for FGFR3 and PTCH1 germline alterations. We reviewed the literature concerning genetic FGFR3 alterations in seborrhoeic keratosis. RESULTS: Individuals of all generations affected by familial seborrhoeic keratosis also presented other skin tumours that corresponded histologically to reticulated acanthomas without apocrine or sebaceous differentiation, as well as ICBCCs. In addition, two novel germline variants, p.Pro449Ser (c.1345C>T) in FGFR3 and p.Pro725Ser (c.2173C>T) in exon 14 of PTCH1 were identified in five participants. CONCLUSIONS: We characterize for the first time the clinical, dermoscopic and histopathological features of multiple reticulated acanthomas without apocrine or sebaceous differentiation, for which we propose the term 'pure reticulated acanthoma', and ICBCCs associated with familial seborrhoeic keratosis. We identified FGFR3 and PTCH1 germline polymorphisms whose influence in the development of reticulated acanthomas is unknown.

Genetic alterations in seborrheic keratoses.

Seborrheic keratoses are common benign epidermal lesions that are associated with increased age and sun-exposure. Those lesions despite harboring multiple somatic alterations in contrast to malignant tumors appear to be genetically stable. In order to investigate and characterize the presence of recurrent mutations, we performed exome sequencing on DNA from one seborrheic keratosis lesion and corresponding blood cells from the same patients with follow up investigation of alterations identified by exome sequencing in 24 additional lesions from as many patients. In addition we investigated alterations in all lesions at specific genes loci that included FGFR3, PIK3CA, HRAS, BRAF, CDKN2A and TERT and DHPH3 promoters. The exome sequencing data indicated three mutations per Mb of the targeted sequence. The mutational pattern depicted typical UV signature with majority of alterations being C>T and CC>TT base changes at dipyrimidinic sites. The FGFR3 mutations were the most frequent, detected in 12 of 25 (48%) lesions, followed by the PIK3CA (32%), TERT promoter (24%) and DPH3 promoter mutations (24%). TERT promoter mutations associated with increased age and were present mainly in the lesions excised from head and neck. Three lesions also carried alterations in CDKN2A. FGFR3, TERT and DPH3 expression did not correlate with mutations in the respective genes and promoters; however, increased FGFR3 transcript levels were associated with increased FOXN1 levels, a suggested positive feedback loop that stalls malignant progression. Thus, in this study we report overall mutation rate through exome sequencing and show the most frequent mutations seborrheic keratosis.

White Papules on the Backs of a Middle-Aged Man and His Son.

A middle-aged man came in for evaluation of "white spots" on his upper body. The number of lesions had increased progressively over the past 20 years but were asymptomatic. The patient expressed concern that his young son had recently developed similar lesions on the upper part of his back. Physical examination revealed numerous, slightly elevated, flat-topped papules scattered over the back, chest, and upper extremities (Figure 1). Each 4- to 6-mm papule was oval or round, ivory white, with a cobblestone surface. The patient's son was also examined and found to have six papules scattered across the upper part of his back and legs, identical in morphology to those of our patient. A shave biopsy was taken from of one of the papules. Results from routine hematoxylin-eosin, as well as Melan-A sections, are shown (Figure 2). The diagnosis was familial keratosis alba or familial hypochromic seborrheic keratosis.

Possible Involvement of F1F0-ATP synthase and Intracellular ATP in Keratinocyte Differentiation in normal skin and skin lesions.

The F1F0-ATP synthase, an enzyme complex, is mainly located on the mitochondrial inner membrane or sometimes cytomembrane to generate or hydrolyze ATP, play a role in cell proliferation. This study focused on the role of F1F0-ATP synthase in keratinocyte differentiation, and its relationship with intracellular and extracellular ATP (InATP and ExATP). The F1F0-ATP synthase ß subunit (ATP5B) expression in various skin tissues and confluence-dependent HaCaT differentiation models was detected. ATP5B expression increased with keratinocyte and HaCaT cell differentiation in normal skin, some epidermis hyper-proliferative diseases, squamous cell carcinoma, and the HaCaT cell differentiation model. The impact of InATP and ExATP content on HaCaT differentiation was reflected by the expression of the differentiation marker involucrin. Inhibition of F1F0-ATP synthase blocked HaCaT cell differentiation, which was associated with a decrease of InATP content, but not with changes of ExATP. Our results revealed that F1F0-ATP synthase expression is associated with the process of keratinocyte differentiation which may possibly be related to InATP synthesis.

Sustained Akt Activity Is Required to Maintain Cell Viability in Seborrheic Keratosis, a Benign Epithelial Tumor.

Seborrheic keratoses (SKs) are common benign skin tumors that share many morphological features with their malignant counterpart, squamous cell carcinoma. SKs frequently have acquired oncogenic mutations in the receptor tyrosine kinase/phosphatidylinositol 3-kinase/Akt signaling cascade. We developed a reliable culture system to study SKs in vitro and screened these cells using a library of selective kinase inhibitors to evaluate effects on cell survival. These benign tumors are sensitive to inhibition by ATP-competitive Akt inhibitors, including A-443654 and GSK690693. RNA interference-mediated Akt suppression mimicked the effects of enzyme inhibition in cultured cells. Akt inhibition suppressed phosphorylation of downstream targets of Akt kinase that are critical for cell survival, including MDM2 and FOXO3a, and induced apoptosis. Cell death was also dependent on p53, mutations in which, although common in cutaneous squamous cell carcinoma, have not been identified in SKs. Intact explants of SKs were also sensitive to Akt inhibition. In addition to the obvious therapeutic implications of these findings, identifying the signaling characteristics that differentiate benign and malignant tumors may inform our understanding of the malignant state.

Segmentally arranged seborrhoeic keratoses with impending atypia and squamous cell carcinoma in an elderly woman.

Epidermal naevi (EN) are considered mosaic disorders. Postzygotic mutations are thought to occur during early embryogenesis. They are usually arranged along Blaschko's lines and tend to be noted either at birth or shortly thereafter. Skin tumours arising on EN are occasionally reported, with ongoing discussion as to whether these are collision tumours or a malignant transformation of the EN. We describe a 76-year-old woman with segmentally arranged seborrhoeic keratoses that showed impending atypia and, in one lesion, even overt malignant transformation. In biopsies from various lesions we found FGFR3 and PIK3CA hotspot mutations but there was no consistent pattern of mutations explaining the premalignant or malignant growth. So far it is unclear whether the precancerous changes as noted in this elderly patient can be taken as an unusual manifestation of one of the established types of EN, or whether this may represent a separate disorder that could be called 'SASKIA naevus'. The acronym would stand for segmentally arranged seborrhoeic keratoses with impending atypia.

Vestigios / Residual findings

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[Genetic basis of seborrheic keratosis and epidermal nevi]. / Genetische Grundlagen seborrhoischer Keratosen und epidermaler Nävi.

Seborrheic keratosis (SK) and epidermal nevi (EN) represent benign skin tumors and congenital lesions, respectively. Oncogenic mutations are fundamentally involved in their pathogenesis and SK is characterized by a broad spectrum of somatic mutations in the FGFR3, PIK3CA, RAS, AKT1 and EGFR genes. In contrast to malignant tumors, SK is genetically stable without alterations of tumor suppressor genes. The ENs are caused by postzygotic activating hot spot mutations in FGFR3, PIK3CA and particularly HRAS, resulting in a genetic mosaicism. The size of the lesions and the differentiation potential of the mutated cell into various tissue types depends on the time point of the mutation during embryogenesis. The genetic mosaic may predispose to a later growth of benign and malignant (adnexal) tumors.

Distinct protein expression and activity of transglutaminases found in different epidermal tumors.

We investigated protein expression and in situ activity of transglutaminases (TGs) in normal skin and various epidermal neoplasms. In normal skin, TG1 protein expression and TG activity were found at keratinocyte cell membranes in upper epidermis and granular layer, respectively. In seborrhoeic keratosis, TG1 protein was expressed evenly throughout tumors, while TG activity increased in gradient fashion from lower tumor area to cornified layer. In squamous cell carcinoma, TG1 protein was expressed at inner side of cell membranes, whereas TG activity was found in cytoplasm predominantly at horn pearls. In basal cell carcinoma, weak TG activity was found in cytoplasm of all tumor cells without the presence of TG1 protein. Immunoblotting and in situ activity assays using specific substrate peptides confirmed that TG2, but not TG1, contributed to the TG activity. These results suggested that different expression and activation of TGs may contribute to characteristics of the skin tumors.

Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors.

Fibroblast growth factor receptor 3 (FGFR3) activating mutations are drivers of malignancy in several human tissues, including bladder, lung, cervix, and blood. However, in skin, these mutations are associated predominantly with benign, common epidermal growths called seborrheic keratoses (SKs). How epidermis resists FGFR3 mediated transformation is unclear, but previous studies have suggested that FGFR3 activation in skin keratinocytes may serve a tumor-suppressive role by driving differentiation and antagonizing Ras signaling. To define the role of FGFR3 in human normal and neoplastic epidermis, and to directly test the hypothesis that FGFR3 antagonizes Ras, we engineered human skin grafts in vivo with mutant active FGFR3 or shRNA FGFR3 knockdown. We show that FGFR3 active mutants drive mild hyperproliferation, but are insufficient to support benign or malignant tumorigenesis, either alone, or in combination with G 1-S checkpoint release. This suggests that additional cell-intrinsic or stromal cues are required for formation of benign SKs with FGFR3 mutations. Further, FGFR3 activation does not alter the growth kinetics or differentiation status of engineered human epidermal SCCs driven by Ras, and FGFR3 protein itself is dispensable for Ras-driven SCC. To extend these findings to patients, we examined a uniquely informative human tumor in which SCC developed in continuity with a SK, raising the hypothesis that one of the tumors evolved from the other. However, mutational analysis from each tumor indicates that the overlapping SK and SCC evolved independently and supports our conclusion that FGFR3 activation is insufficient to drive SCC.

Low incidence of oncogenic EGFR, HRAS, and KRAS mutations in seborrheic keratosis.

Seborrheic keratosis (SK) represents a frequent epidermal skin tumor. Although lacking a malignant potential, these tumors reveal multiple oncogenic mutations. A previous study identified activating mutations in 89% of SK, particularly in FGFR3 and PIK3CA genes. The aim of this study was to identify further oncogenic mutations in human SK. Therefore, we screened for mutations in EGFR, FGFR2, PIK3R1, HRAS, KRAS, and NRAS genes using both Sanger sequencing of selected exons and a multiplex SNaPshot assay in 58 SK of 14 patients. We identified a somatic EGFR p.L858R mutation in 1 SK. Furthermore, the HRAS mutations p.G13R (2/58 SK) and p.Q61L (2/58 SK) were found. These mutations have not been described in human SK yet. In addition, 1 SK revealed the KRAS p.G12V mutation, which has already been reported in SK. No mutations were detected in FGFR2, PIK3R1, and NRAS genes. The results of this study suggest that activating mutations of EGFR, HRAS, and KRAS contribute to the pathogenesis of human SK, although at a lower frequency than FGFR3 and PIK3CA mutations. FGFR2, PIK3R1, and NRAS mutations obviously do not have a significant role in the development of SK.