Seborrheic Keratosis Research Articles

A Case of Seborrheic Keratosis of Cavum Concha

Seborrheic keratosis is a common type of epidermal tumor caused by benign proliferation of immature keratinocytes. They usually appear as well-demarcated, slightly raised brownish patches or plaques. They are typically slow-growing, can increase in thickness over time, and rarely resolved spontaneously. Seborrheic keratosis is frequently found on sun-exposed skin surfaces such as the trunk, extremities, head and neck of elderly people. However, it is rare to find these lesions in the auricle or external auditory canal. In addition, seborrheic keratosis is often distinguished as a benign tumor, but there can be some morphological overlap with other malignant skin lesions. Herein, we report, along with a literature review, a case of seborrheic keratosis in a patient who presented with a mass in the left cavum concha with a sudden increase in size.

Leser-Trélat Sign in Association With Diffuse Large B-Cell Lymphoma: A Case Report

Introduction: The Leser-Trélat sign is a paraneoplastic skin syndrome characterized by the sudden eruption of pruritic seborrheic keratoses in association with underlying carcinoma. Herein, we report a rare case of the Leser-Trélat sign in association with B-cell lymphoma. Case presentation: A 76-year-old man presented at our hospital with lower back/abdominal pain and a sudden eruption of black papules at multiple sites. Contrast-enhanced CT indicated a solid abdominal mass with multiple metastases. The histopathological examination of a lymph node biopsy led to a diagnosis of diffuse large B-cell lymphoma. A biopsy of the black papules confirmed the diagnosis of seborrheic keratoses. Discussion: The clinical and histological findings supported the diagnosis of the Leser-Trélat sign. The seborrheic keratoses were skin manifestations of diffuse large B-cell lymphoma. Conclusion: Clinicians should be aware that the eruption of seborrheic keratoses may be associated with visceral malignancy. To the best of our knowledge, this is the first case report of the Leser-Trélat sign in association with diffuse large B-cell lymphoma.

Micro-relief characterization of benign and malignant skin lesions by polarization speckle analysis in vivo.

A recent direction in skin disease classification is to develop quantitative diagnostic techniques. Skin relief, colloquially known as roughness, is an important clinical feature. The aim of this study is to demonstrate a novel polarization speckle technique to quantitatively measure roughness on skin lesions in vivo. We then calculate the average roughness of different types of skin lesions to determine the extent to which polarization speckle roughness measurements can be used to identify skin cancer. The experimental conditions were set to target the fine relief structure on the order of ten microns within a small field of view of 3 mm. The device was tested in a clinical study on patients with malignant and benign skin lesions that resemble cancer. The cancer group includes 37 malignant melanomas (MM), 43 basal cell carcinomas (BCC), and 26 squamous cell carcinomas (SCC), all categories confirmed by gold standard biopsy. The benign group includes 109 seborrheic keratoses (SK), 79 nevi, and 11 actinic keratoses (AK). Normal skin roughness was obtained for the same patients (301 different body sites proximal to the lesion). The average root mean squared (rms) roughness ± standard error of the mean for MM and nevus was equal to 19 ± 5 μm and 21 ± 3 μm, respectively. Normal skin has rms roughness of 31 ± 3 μm, other lesions have roughness of 35 ± 10 μm (AK), 35 ± 7 μm (SCC), 31 ± 4 μm (SK), and 30 ± 5 μm (BCC). An independent-samples Kruskal-Wallis test indicates that MM and nevus can be separated from each of the tested types of lesions, except each other. These results quantify clinical knowledge of lesion roughness and could be useful for optical cancer detection.

Benign Keratosis: A Useful Term?

Seborrheic keratosis (SK), lichen planus-like keratosis (LPLK), and solar lentigo (SL) are common benign skin lesions. These lesions are frequently seen adjacent to each other or can arise from one another. They can sometimes be difficult to differentiate despite having distinct histopathological features. We evaluated dermoscopic images of 80 skin lesions to confirm the term 'benign keratosis' is useful for an undifferentiated SK/LPLK/SL where there are overlapping clinical and dermoscopic characteristics. Clinical and dermoscopic images were sourced from a teledermoscopy service database of 13,000 lesions in 7,000 patients. The database was queried for SK, SL or LPLK in sun-exposed sites. Each lesion was evaluated based on specific dermoscopic criteria and the results analyzed. Lesions were identified with mixed clinical and dermoscopic criteria of SK and SL, and in some, dermoscopic criteria for LPLK were also present. This study highlights the relationship between these lesions. We confirm the term 'benign keratosis' is useful for mixed lesions or for those that are difficult to classify.

Correlation between Superoxide Dismutase (SOD) with Malondialdehyde (MDA) level in blood plasma of seborrheic keratosis

Introduction: Seborrheic keratosis (SK) is a benign tumor of the epidermis, its development is associated with various hypotheses, but none came out as the main culprit. A few study results regarding the oxidative stress strongly associated with skin tumors have been reported. Superoxide dismutase (SOD) is a potent protective enzymatic antioxidant. Malondialdehyde (MDA) is the end product of lipid peroxidation produced by free radicals in the body. Increased levels of MDA usually accompany low levels of antioxidants. Methods: This study was an observational analytic study with a cross-sectional method involving 42 seborrheic keratosis subjects based on inclusion and exclusion criteria. We recorded the gender, age, family history, and occupation of the subjects. Diagnosis of seborrheic keratosis was made based on history taking and clinical examination—measurement of SOD level by ELISA method and MDA levels by TBARS method. The Spearman correlation test was measured and was considered significant if the p-value was <0.05. Results: Seborrheic keratosis was more common in females (92.9%), with the most common age group being 40 ̶ 50 years old (57.1%), had a family history of SK (26.2%), and worked in agriculture, forestry, and fisheries (26.2%). The average blood plasma SOD level was 1.68 mmol/L, and the blood plasma MDA level was 181.19 U/L. The correlation coefficient between blood plasma SOD levels and blood plasma MDA levels was -0.393, with a significant value of p=0.01. This study showed that the lower the SOD level, the higher the MDA level in the blood plasma of seborrheic keratosis. Conclusion: There is a significant correlation between SOD and MDA levels in the blood plasma of seborrheic keratosis subjects.

Clinico-Pathological Profile of Basaloid Skin Tumors-Experience from a Tertiary Care Center of Eastern India.

Basaloid tumors comprise a wide spectrum of benign and malignant tumors like basal cell carcinoma, seborrheic keratosis, pilomatricoma, basosquamous carcinoma, trichoblastoma, and cylindroma. Among them, basal cell carcinoma is the most common type which constitutes about 90% of all malignant skin tumor. This study was aimed at analyzing the clinico-pathological profile of basaloid skin tumors attending radiotherapy and surgery OPD of our institution and compares them with those of the reported literature from rest of the country as well as outside world. All cases of basaloid skin tumors presented at radiotherapy, surgery, and dermatology OPD between January 2020 and June 2021 with or without a histological diagnosis were evaluated. Those without a histological diagnosis underwent biopsy and categorized according to standard histological criteria. After histological confirmation, we collected demographic, clinical, and pathological data of the cases. Among 106 patients analyzed, 54.7% (58) cases were diagnosed as basal cell carcinoma followed by seborrheic keratosis (17.9%), pilomatricoma (13.2%), basosquamous carcinoma (9.4%), trichoblastoma (2.8%), and cylindroma (1.8%). Mean age of presentation was 57.03 (± 7.435) years, and head-neck region was the most common site of involvement for basal cell carcinoma. Twenty-two cases required immunohistochemical assessment for confirmation of diagnosis. To conclude, this study is one of its first from Eastern India and will act as a stepping stone for future studies concentrating on clinico-pathological profile, early diagnosis and treatment of basaloid skin tumors.

APPLICATION FOR SKIN DISEASE DIAGNOSIS SYSTEM USING CONVNET

Skin disease among humans has been a common disease, millions of people are suffering from various kinds of skin diseases. Usually, these diseases have hidden dangers which lead to not only lack of self- confidence and psychological depression but also lead to a risk of skin cancer. Medical experts and high- level instruments are needed to diagnosis these skin diseases due to non-availability of visual resolution in skin disease images. The proposed framework includes deep learning techniques such as CNN architecture and three predefined models called Alex Net, ResNet, InceptionV3. A Dataset of images with seven diseases has been taken for the Classification of Skin diseases. They include diseases like Melanoma, Nevus, Seborrheic Keratosis etc. The dataset was extended by adding images having cuts and burns, which were classified as skin disease by most of the existing systems. The usage of Deep Learning algorithms has reduced the need for human labor, such as manual feature extraction and data reconstruction for classification purposes. In this project we develop a use doctor interaction portal to show skin disease prediction module with CNN and doctor appointment booking and user- friendly chat bot. Keywords—Diagnosis, CNN, Alex Net, ResNet, InceptionV3, Deep learning Algorithms, Chatbot.

Acenocoumarol, an Anticoagulant Drug, Prevents Melanogenesis in B16F10 Melanoma Cells.

Hyperpigmentation can occur in abnormal skin conditions such as melanomas, as well as in conditions including melasma, freckles, age spots, seborrheic keratosis, and café-au-lait spots (flat brown spots). Thus, there is an increasing need for the development of depigmenting agents. We aimed to repurpose an anticoagulant drug as an effective ingredient against hyperpigmentation and apply cosmeceutical agents. In the present study, the anti-melanogenic effects of two anticoagulant drugs, acenocoumarol and warfarin, were investigated. The results showed that both acenocoumarol and warfarin did not cause any cytotoxicity and resulted in a significant reduction in intracellular tyrosinase activity and melanin content in B16F10 melanoma cells. Additionally, acenocoumarol inhibits the expression of melanogenic enzymes such as tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2, suppressing melanin synthesis through a cAMP-dependent, protein kinase (PKA)-dependent downregulation of microphthalmia-associated transcription factor (MITF), a master transcription factor in melanogenesis. Furthermore, anti-melanogenic effects were exerted by acenocoumarol through downregulation of the p38 and JNK signaling pathway and upregulation of extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/glycogen synthesis kinase-3β (GSK-3β) cascades. In addition, the β-catenin content in the cell cytoplasm and nucleus was increased by acenocoumarol through a reduction in the phosphorylated β-catenin (p-β-catenin content). Finally, we tested the potential of acenocoumarol for topical applications by conducting primary human skin irritation tests. Acenocoumarol did not induce any adverse reactions during these tests. Based on the results, it can be concluded that acenocoumarol regulates melanogenesis through various signaling pathways such as PKA, MAPKs, PI3K/Akt/GSK-3β, and β-catenin. These findings suggest that acenocoumarol has the potential to be repurposed as a drug for treating hyperpigmentation symptoms and could provide new insights into the development of therapeutic approaches for hyperpigmentation disorders.

Leser–Trelat sign in cosmetologist’s practice

LeserTrelat syndrome (eruptive seborrheic keratosis) is an unusial paraneoplastic dermatosis characterized by sudden appearance of seborrheic keratomas on the skin and a progressive increase of their number. This condition was first described in 1901 by the German surgeon E. Leser and the French surgeon U. Trelat. It occurs with the same frequency in both men and women aged 40+. The etiology and pathogenesis have not been studied in detail, however, there is evidence that the development of the syndrome may be associated with stimulation of the epidermal growth factor, which leads to stimulation of keratinocytes. The manifestation of the syndrome is usually start at the same time with cancer development, mostly it can be combained with adenocarcinoma of the gastrointestinal tract (47.7%), with intestinal carcinoma (32%), with lymphoproliferative diseases (21%), less often with malignant neoplasms of the lungs, breast, prostate.
 The clinical picture of the LeserTrelat sign is characterized by the sudden appearance оf seborrheic keratomas, which have typical clinical and histological signs. The most typical localization of seborrheic keratosis are back and chest (76%), limbs (18%), face (21%), abdomen (15%), neck (13%), armpits (6%), inguinal folds (3%). Keratosis can appear rapidly, over several months or even weeks. The rapid appearance of multiple seborheic keratomas may precede or develop with the oncological process in the internal organs.
 Treatment is carried out at the same time with the establishment and treatment of the underlying disease and consists in removing the largest keratomas by destructive methods (surgical excision, radiowave method, cryodestruction, electrocoagulation).
 The prognosis is favorable if paraneoplastic process was early detected.
 The article describes clinical cases of multiple seborrheic keratosis and the tactics of examining this group of patients.

Nevoid Hyperkeratosis of the Nipple – A Case Report and Review of Literature

Nevoid hyperkeratosis of the nipple and areola (NHNA) is a rare, benign, idiopathic condition, which occurs predominantly in women of child-bearing age. It is characterized by asymptomatic, hyperkeratotic, verrucous plaques, and either unilateral or bilateral over the nipple and areola. It has to be differentiated from Darier disease, seborrheic keratosis, atopic dermatitis, Paget’s disease, frictional hyperkeratosis, and cutaneous T-cell lymphoma. Fused rete ridges, compact orthohyperkeratosis, and filiform papillomatosis are seen on histopathology. Dermoscopy shows keratotic structureless areas with brownish clods. There is no specific treatment, long-term use of calcipotriol and keratolytic agents for more than 6 months, and surgical therapy is recommended. This case is reported to highlight the use of dermoscopy in the diagnosis of NHNA.

Skin diseases of the nipple and areola complex: A case series study from China.

Skin diseases of the nipple and areola complex (NAC) are numerous and difficult to diagnose, which is a great challenge for clinicians. A better understanding of the clinical features of NAC skin diseases is of great value for the correct diagnosis. To investigate the clinical characteristics of skin diseases of the NAC, we retrospectively analyzed the demographic data, disease constitution, rash characteristics, inconsistency between the clinical and pathological diagnosis from 260 patients with NAC lesions that were confirmed by histopathology at Peking Union Medical College Hospital, China from 2012 to 2022. The patients' average age was 43.6 (8 to 82) years, and the ratio of females to males was 13.4:1. Out of the 260 patients biopsied, the most common diseases were eczema, Paget's disease (PD), adenoma of the nipple (AN), seborrheic keratosis (SK), cutaneous metastasis of breast cancer, wart, soft fibroma, and hyperkeratosis of the nipple and areola. There were 77 (29.6%) patients with inconsistency between the clinical impressions and pathological diagnoses. AN was the most clinically misdiagnosed condition, most commonly presumed to be PD or eczema. Eczema and PD are the most common biopsied NAC skin diseases. Late onset, unilateral involvement, and predilection for the nipple are several characteristics of PD, which are different from eczema. NAC skin diseases are easily misdiagnosed clinically, especially AN.

An epidemiological study on skin tumors of the elderly in a community in Shanghai, China

The morbidity of skin tumors (ST) in China is a great concern as the population ages. No epidemiological survey on ST in elderly communities in China has been reported. A questionnaire survey was conducted among the residents over 60 years old in a community in Shanghai, China from May 1, 2011 to November 30, 2011. The prevalence of cutaneous tumors and associated factors were analyzed. Among 2038 valid cases, a total of 78 (3.8%, 95% CI 3.0–4.7) skin cancers (SC) were confirmed. According to the final multivariate regression analysis, age, gender and previous occupation were the significantly influential factors for SC. Actinic keratosis (AK) accounted for the largest proportion (63, 3.1%) in SC. The head and neck was the physiological site with the highest incidence of SC (64, 82.1%), and AK was the most common (55, 87.3%) in head and neck SC. The common concomitant diseases of SC were hypertension (26, 33.3%) and diabetes mellitus (9, 11.5%). Seborrheic keratosis (SK) was the most common benign skin tumor with a prevalence of 100%. Men and women developed SK in significantly different parts of the body (P < 0.0001). The incidence of ST in the elderly population in Shanghai community increased with age. ST preferred to occur in the head and neck, which might be attributed to excessive ultraviolet (UV) exposure in these areas. Therefore, early diagnosis and sun-protection education are essential interventions for ST in the elderly.

Unusual site of a common skin lesion - Seborrheic keratosis

Seborrheic keratosis is common benign cutaneous tumour in the elderly which usually presents as pigmented lesion with stuck on appearance. It is seen on the head and neck region. Ear is an uncommon site for Seborrheic keratosis. Seborrheic keratosis is associated with sun- exposure, HPV and mutations in the FGFR3 and PIK3CA gene, but the pathophysiology is still not very clearly understood. We present a case in 60 years old lady who presented with a dark brown pigmented, cerebriform growth in the concha near the external auditory canal associated with reduced hearing and discharge on and off. Clinical suspicion was keratoacanthoma but the histopathological examination showed irritated and pigmented variant of Seborrheic keratosis. Seborrheic keratosis seldom needs to be treated since most of the patients are asymptomatic and get treated for cosmetic purpose but in this present case the patient was symptomatic, hence the mass was excised.

Enlarged rete pegs with excessive accumulation of melanosomes leading to darker aging spots revealed by histomorphological measurements of internal structures of the epidermis.

Various histological studies of facial pigmented spot sites such as solar lentigo have been reported, but few studies have used quantitative indices by histomorphometric analysis of the internal structure of pigmented spot sites using non-invasive methods. In the present study, to quantitatively elucidate morphological changes in the epidermis in male, darker-pigmented spots and female, light-pigmented spots, indices that characterize the internal structure of the epidermis in pigmented spot sites were measured using in vivo confocal laser scanning microscopy (CLSM). The darkness of pigmented spots on the cheeks of 69 women and 43 men was analysed using image analysis software. The L* value was calculated from RGB values obtained from facial images. The internal structures of pigmented spots on the cheeks of 13 subjects were observed by CLSM. Various parameters were measured using CLSM images from the surface of the stratum corneum to the bottom of the dermal papillae, including the thickness of the epidermis, melanosome content, and shape of the dermal papillae. Mean ΔL* values between pigmented spots and non-pigmented areas of male subjects were significantly increased in the 40s and 50s compared with those of female subjects. Conspicuous pigmented spots increased in the 40s in male subjects and the 50s in female subjects. In CLSM observations, significant increases in the thickness of the epidermis and melanosome content were confirmed in pigmented spots compared with surrounding non-pigmented areas. In particular, melanosome content in the male subject group with dark-coloured pigmented spots increased significantly to about eight times that of non-pigmented areas, and more than double that of the male subject group with light-coloured pigmented spots. From the measurements of quantitative parameters, morphological changes in the epidermis were clearly related to the surface colour tone of pigmented spots. Darker pigmented spot sites tended to show longer rete pegs in the epidermis. Accumulation of melanosomes in epidermal basal cells could be considered to increase with the degree of elongation of rete pegs at pigmented spot sites and, thus, induce darker pigmented spots.

Studies on Different CNN Algorithms for Face Skin Disease Classification Based on Clinical Image

Skin problems not only injure physical health but also induce psychological problems, especially for patients whose faces have been damaged or even disfigured. Using smart devices, most of the people are able to obtain convenient clinical images of their face skin condition. On the other hand, the convolutional neural networks (CNNs) have achieved near or even better performance than human beings in the imaging field. Therefore, this paper studied different CNN algorithms for face skin disease classification based on the clinical images. First, from Xiangya–Derm, which is, to the best of our knowledge, China’s largest clinical image dataset of skin diseases, we established a dataset that contains 2656 face images belonging to six common skin diseases [seborrheic keratosis (SK), actinic keratosis (AK), rosacea (ROS), lupus erythematosus (LE), basal cell carcinoma (BCC), and squamous cell carcinoma (SCC)]. We performed studies using five mainstream network algorithms to classify these diseases in the dataset and compared the results. Then, we performed studies using an independent dataset of the same disease types, but from other body parts, to perform transfer learning on our models. Comparing the performances, the models that used transfer learning achieved a higher average precision and recall for almost all structures. In the test dataset, which included 388 facial images, the best model achieved 92.9%, 89.2%, and 84.3% recalls for the LE, BCC, and SK, respectively, and the mean recall and precision reached 77.0% and 70.8%

Clinicopathological analysis of eyelid lesions in Sri Lanka.

We intended to review the clinical features and histological findings of eyelid lesions in Sri Lanka. We conducted a descriptive cross-sectional study to analyse clinicopathological characteristics of eyelid lesions from 2013 to 2017 in the National Eye Hospital of Sri Lanka. The age of patients ranged from 3months to 83years (mean = 46 ± 21years). The male-to-female ratio in the sample was 1:1.3. Among 654 histologically confirmed eyelid lesions, the majority (n = 407/654, 62%) were neoplastic lesions including 322 benign, 11 premalignant and 74 malignant neoplasms. The commonest benign tumour was seborrheic keratosis (n = 98), and the commonest non-neoplastic lesion was pyogenic granuloma (n = 64). Seventy-four patients had malignant neoplasia including 24 sebaceous carcinoma, 18 basal cell carcinoma, and 14 squamous cell carcinoma. The most common site of malignant lesions was the upper eyelid. The mean age of patients with malignant eyelid lesions was 64 ± 13years. Neoplastic lesions outnumbered nonneoplastic lesions, while benign neoplasia was more common than malignant neoplasia. In contrast to the western reports, the commonest malignant neoplasm was sebaceous carcinoma.

A Two-Stage End-to-End Deep Learning Framework for Pathologic Examination in Skin Tumor Diagnosis

Neurofibromas (NF), Bowen's disease (BD), and Seborrheic Keratosis (SK) are common skin tumors. Pathological examination is the golden standard for diagnosis of these tumors. Current pathological diagnosis is mainly based on the observation of naked eyes under microscope, which is laborious and time-consuming. Digitization of pathology brings the opportunity for AI technology to improve the efficiency of diagnosis. This research aims to develop an end-to-end extendable framework for the diagnosis of skin tumor based on pathological slide image. NF, BD, SK were selected as target skin tumors. A two-stage skin cancer diagnosis framework (TSSD) is proposed in this paper, which consists of two parts: patches-wise diagnosis and slide-wise diagnosis. Patches-wise diagnosis compares different Convolutional Neural Networks (CNN) to extract features and distinguish categories from patches generated in whole slide images. Slide-wise diagnosis combines Attention Graph Gated Network (AGGN) model prediction with post-processing algorithm. This approach can fuse information from feature embedding learning and domain knowledge to draw a conclusion. Training, validation and testing were performed on NF, BD, SK and negative samples. Accuracy and ROC curves were used to evaluate the classification performance. This study investigated on the feasibility of skin tumor diagnosis in pathological image and may be the first time that deep learning is applied to address these three kinds of tumor diagnosis in skin pathology.

The differential diagnosis of lichenoid keratosis and seborrheic keratosis with reflectance confocal microscopy: a preliminary study.

Lichenoid keratosis (LK, or lichen planus-like keratosis, LPLK) and seborrheic keratosis (SK) present as similar benign keratotic lesions on cosmetically sensitive area, but require different therapies. Both lesions can be easily differentiated based on histological evaluation of biopsy materials. However, the biopsies may cause scarring and result in hyper-pigmentation, which reduces the compliance of the patients to be treated. In this study, we investigated the role of reflectance confocal microscopy (RCM) in the non-invasive differential diagnosis of LK and SK. Cases with facial brown patches or plaques suspicious of SK were enrolled in the study. After written informed consent was obtained, the lesions were photographed, imaged by RCM, and then biopsied. The RCM findings were analyzed and correlated with histology results. Evaluation of the RCM pictures and confirmation with histological results were conducted by two independent dermatologists. In total, 10 cases were enrolled in the study. The main characteristics of LK lesions observed by RCM were the disarray of the dermal-epidermal junction (DEJ), and marked inflammatory infiltrates in the superficial dermis; while prominent cerebriform pattern, or elongated cords with bulbous projections without significant inflammation reaction, were the features of SK. Among the 10 cases, clinically suspicious of facial SK, 4 were determined as LK, 6 as SK by RCM imaging, and all the RCM findings were confirmed by histological results. The RCM features of LK and SK have significant difference, highlighting the important role of RCM in the differential diagnosis of LK and SK, avoiding biopsies and allowing safe treatments.

Seborrheic Keratosis Caused by Human Papillomavirus Type 20 Ameliorated by Zinc Oxide Ointment

A 91-year-old woman visited our department with scattered small nodule lesions and multiple pules or plaques with a stuck-on appearance. The lesions were intractable and resistant to several treatments. Immunodeficiency was excluded by examinations including a CT scan, white blood cell (WBC) counts, natural killer and neutrophil function assays, and IgG titers against human papillomavirus (HPV) 20. HPV20 was identified using the PCR method. The finding of the skin biopsy showed an irritated type of feature of seborrheic keratosis. Additionally, immunohistochemical staining of the lesion revealed that both TNF-α and IFN-ɤ were produced at the skin lesions. The patient's serum zinc level was slightly low. We noticed that zinc deficiency has been reported to decrease the cytotoxic activity of natural killer cells, which play an important role in eliminating virus-infected cells and tumor cells. Finally, zinc oxide ointment was found to improve the lesions dramatically. HPV20 causes tumors only in immunodeficient patients or in patients with epidermodysplasia verruciformis (EV). In EV, EVER1- or EVER2-encoding membrane proteins, of which are related to zinc transport protein-1 expressed on the membrane of the endoplasmic reticulum, were mutated, leading to increased susceptibility to various viral and bacterial infections due to the decreased intracellular zinc concentration. We speculated that the reduction in local zinc concentration was ameliorated by using zinc oxide ointment, resulting in the recovery from HPV20 infection.

Reply to Montastruc et al.

To the Editor—We thank Drs Montastruc and de Canecaude for their comments [1]. Immortal time bias implicates a study design wherein participants cannot experience the outcome during some period of follow-up time. Montastruc et al posit that immortal time bias impacts our study and limits the significance of our results by generating an illusion of protective effect. The concern stems from a belief that both our exposure and control cohorts were composed of persons diagnosed with acne, seborrheic keratosis, or melanocytic nevi (A/Sk/Mn). If this were the study design, participants allocated to the exposure group would include an “immortal” time period between A/Sk/Mn diagnosis and the exposure (T&C administration), increasing the observation window for the unexposed group (which now includes the exposure group prior to exposure), and decreasing the cardiovascular event rate in the unexposed. This could lead to an observation of a higher cardiovascular event rate, and thus immortal time bias could be implicated in our results.