Epidermodysplasia verruciformis-associated eccrine neoplasm: a rare entity with distinctive clinical and histopathologic features.

Most tumors are caused by inherited or acquired genetic changes. However, a subset of tumors is driven by viral infection including Kaposi sarcoma, nasopharyngeal carcinoma, and others. Human papillomavirus (HPV) is an especially common cause of epithelial cancers and hyperplasias. Epidermodysplasia verruciformis (EDV) is a rare type of HPV infection with characteristic histopathologic features and a unique spectrum of HPV subtypes. We report here a distinctive form of EDV-associated eccrine neoplasia. Seven tumors from two patients were analyzed and show highly uniform features including multiple clustered clinical lesions, multifocal epidermal origin, eccrine differentiation with close association with the acrosyringium, an anastomosing growth pattern, and a bland monotonous poroid-to-basaloid cytomorphology. Clinical follow-up for one patient has been benign to date. These tumors show strong similarity to two previously reported cases, suggesting that this type of EDV-associated eccrine neoplasia may represent a rare but reproducible form of skin adnexal tumor with distinctive clinicopathologic features.

STK4 deficiency and epidermodysplasia verruciformis-like lesions: A case report.

Serine/threonine kinase 4 deficiency (STK4 or MST1, OMIM:614868) is an autosomal recessive (AR) combined immunodeficiency that can present with skin lesions such as epidermodysplasia verruciformis-like lesions (EVLL). Herein, we describe a 17-year-old male patient born from consanguineous parents presenting with recurrent respiratory infections, verruciform plaques, poikiloderma, chronic benign lymphoproliferation, and Sjögren syndrome with suspected interstitial lymphocytic pneumonia.

Epidermodysplasia Verruciformis: A Study of Clinicopathologic Features, Biomarkers, and Associated Malignancies in Indian Patients.

BACKGROUND: Epidermodysplasia verruciformis (EDV) is a rare cutaneous manifestation of human papilloma virus infection, which has a potential for malignant transformation. The characteristic histologic features of EDV may not always be present and may often be overlooked. The use of a panel of novel biomarkers may aid in differentiating EDV from their clinical and pathologic mimics. MATERIAL AND METHODS: We reviewed 20 cases histologically diagnosed as EDV from 2013 to 2022. Sections were reviewed for histopathologic features, and immunohistochemistry for p16 and Ki67 was performed. RESULTS: There were 20 cases, ranging in age from 6 to 52 years with a male predominance. Four patients were immunosuppressed, and 4 patients had a positive family history. The most common presentation was hypopigmented papules and macules. In all the cases, epidermal keratinocytes showed dysmaturation, enlargement, and a blue-gray cytoplasm. These changes were very focal and superficial in 15 cases (75%). Associated malignancies included carcinoma in situ (1), trichilemmoma (2), and trichilemmal carcinoma (1). The trichilemmal tumors were seen in 2 siblings. p16 was expressed in the parabasal and basal layers in 7 of 17 cases (41%), in keratinocytes with and without inclusions. Ki67 was increased and localized to suprabasal and parabasal keratinocytes in 15 of 17 cases (88%). CONCLUSION: Although striking and characteristic, the keratinocyte changes are often focal and superficial, requiring multiple step-sections. Association of EDV with familial trichilemmal neoplasms is a novel finding requiring further genetic testing. In cases of clinically suspected EDV with negative histopathologic findings, p16 and Ki67 seem useful as adjunct biomarkers and could serve as cost-effective alternatives to genotyping.

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.

Condyloma and coincidental epidermodysplasia verruciformis acanthoma positive for human papillomavirus-14 and -21.

Epidermodysplasia verruciformis (EDV) is a rare genodermatosis that predisposes individuals to persistent infection with ß-human papillomavirus (HPV) genotypes. The term EDV acanthoma may be applied to lesions with incidental findings of EDV-defining histopathological features without clinical signs of EDV. We report a case of HPV-14- and -21-positive EDV acanthoma arising in association with condyloma in a female patient with a history of low-grade squamous intraepithelial lesion of the cervix positive for high-risk HPV (non-16/18), chronic kidney disease, and systemic lupus erythematosus. The patient had no family or personal history of EDV, but the patient was on immunosuppressive therapy with mycophenolate mofetil and prednisone. A biopsy specimen from one of the perianal lesions revealed histopathologic changes consistent with EDV in the setting of condyloma. Molecular testing showed HPV-14 and -21, which supported the coexistence of condyloma with EDV acanthoma.

Establishment of a human induced pluripotent stem cell line, KMUGMCi005-A, from a patient with Epidermodysplasia verruciformis (EV) bearing homozygous splicing donor site mutation in the TMC8 gene.

Epidermodysplasia verruciformis (EV) is an autosomal recessive dermatosis characterized by abnormal susceptibility to human beta papillomaviruses and a high rate of progression to squamous cell carcinoma on sun-exposed skin. The majority of EV cases are caused by homozygous mutation in TMC8. The peripheral blood mononuclear cells from a patient carrying homozygous mutation of the TMC8 gene were reprogrammed using the CytoTune-iPS2.0 Sendai Reprogramming Kit. The homozygous mutation in TMC8 will cause the abnormal splicing variant, which is known to associated with EV. The established human induced pluripotent cell line will enable proper in vitro disease modelling of EV.

HPV-57 Verruca Vulgaris Mimicking Epidermodysplasia Verruciformis.

ABSTRACT: Human papilloma virus (HPV) is the causative agent for a variety of cutaneous lesions including verruca vulgaris (VV) and epidermodysplasia verruciformis (EDV). There are more than 200 known genotypes of HPV, and specific HPV types are associated with different clinical manifestations and malignant potentials. Herein, we describe a case of a 43-year-old immunocompetent woman who presented with morphologically distinct lesions that were most consistent with EDV on clinical examination. However, further histopathological and viral analysis confirmed the lesions as HPV-57-positive VV. The risk of malignant transformation, and therefore treatment and surveillance, is dramatically different in VV versus EDV. Therefore, this case highlights the importance of a proper histopathological diagnosis with HPV viral testing when clinical presentations may vary or mimic other diseases.

Acquired epidermodysplasia verruciformis in a renal transplant patient: a case report.

Acquired epidermodysplasia verruciformis is a rare disease. It can develop in immunocompromised patients due to infection with human papillomaviruses. Because such patients are at high risk of developing cutaneous squamous cell carcinoma, timely diagnosis and regular monitoring of the patient is essential. Here we present the case of a 46-year-old male patient with acquired epidermodysplasia verruciformis occurring 5 years after a kidney transplantation. A skin biopsy detected human papillomavirus genotype 20 with low oncogenic potential. Accordingly, a follow-up interval of 1 year was determined. He was instructed to follow strict photoprotection and to visit earlier if atypical lesions appeared. Overall, our case emphasizes the consideration of possible squamous cell carcinoma in such patients and the importance of appropriate preventive measures.

TMC8 mutation in a Turkish family with epidermodysplasia verruciformis including laryngeal papilloma and recurrent skin carcinoma.

The vast majority of primary immunodeficiencies (PIDs) occur due to the defects in cells originating from hematopoietic stem cells, while in some PIDs, there are defects in various genes responsible for non-leucocyte immune response such as seen in epidermodysplasia verruciformis (EV). EV caused by the mutations in TMC6, TMC8, and CIB1 genes is called "typical." "Atypical" EV may develop in patients with primary immunodeficiencies originating from hematopoietic stem cells, which include severe T-cell failure, caused by inactivating biallelic mutations of STK4, RHOH, CORO1A, ITK, TPP2, DCLRE1C, LCK, RASGRP1, or DOCK8 genes. Here, we present a family with TMC8 gene mutation leading to disseminated epidermodysplasia verruciformis including laryngeal papilloma and recurrent cutaneous squamous cell carcinomas. Typical EV with impaired local, keratinocyte-intrinsic immune response should be considered when routine immunological examinations are normal in patients presenting with clinical signs of EV. Although it is not possible to prevent EV lesions, early and appropriate surveillance for malignancy is mandatory.

Efflorescence of acquired epidermodysplasia verruciformis due to immune reconstitution inflammatory syndrome-like mechanisms following anti-HPV vaccination in a HIV-positive patient.

Epidermodysplasia verruciformis (EV) is a rare cutaneous pre-cancerous condition characterized by presence of flat, scaly macules, verruca-like papillomatous papules, seborrheic keratosis-like lesions, and pink-red pityriasis versicolor-like macules. The disease is caused by abnormal susceptibility to certain specific beta-HPV subtypes, most commonly 5 and 8. Classic EV is genetically determined, but in immunocompromised individuals, an acquired form can occur. Only 48 cases of acquired EV (AEV) in people living with HIV have been described. We describe a case of AEV in a 36-year-old HIV-positive man with an history of stable optimal CD4 cell count and undetectable HIV viral load. The AEV significantly deteriorated after the administration of the second dose of the quadrivalent anti-HPV vaccine and did not improve despite local treatment, anti-HPV vaccination completion, and persistently optimal combined antiretroviral treatment adherence. To the best of our knowledge, this is the first report of an AEV deterioration with a clinical and temporal pattern mimicking an immune reconstitution inflammatory syndrome (IRIS) following anti-HPV vaccination, instead of low CD4 count restoration. After reviewing the current literature, we have hypothesized a vaccine-mediated IRIS-like phenomenon in the pathogenesis of the disease.

Recurrent fungating tumor and a chronic rash in an immunosuppressed transgender patient: a case of Buschke-Lowenstein condyloma and epidermodysplasia verruciformis.

A transgender female in her 40s with history of HIV and testicular cancer status post-genital X-irradiation presented with a perianal mass and pruritic rash across her chest. Physical examination revealed a bulky, verrucous tumor protruding outward from the anus involving the medial buttocks. Examination of the chest and arms showed numerous guttate, pink, flat-topped papules coalescing into plaques. Clinically and histologically the lesions were consistent with Buschke-Löwenstein condyloma (BLC) and acquired epidermodysplasia verruciformis (AEDV). Buschke-Löwenstein condyloma incisional biopsy tested negative for common low- and high-risk human papillomavirus (HPV) subtypes, including 6, 11, 16, and 18, possibly implicating beta HPV subtype or a less common pathogenic subtype. The patient underwent abdominoperineal resection of the BLC, which tested positive for low-risk HPV subtypes, suggesting the possibility of multiple implicated HPV subtypes in the same tumor. This case demonstrates a possible role of beta HPV or rarer HPV subtypes in the pathogenesis of verrucous carcinoma, particularly in the setting of immunosuppression.

Epidermodysplasia Verruciformis After Hematopoietic Stem Cell Transplantation in a Patient With Severe Combined Immunodeficiency Syndrome.

ABSTRACT: Epidermodysplasia verruciformis (EV) is a rare dermatologic disorder that is characterized by skin-colored-to-light brown flat, discrete or confluent papules resembling verruca plana. EV is divided into 2 forms: a classical genetic form and an acquired form. Classical genetic EV is caused by mutations in EVER1 and EVER2 genes. Acquired EV develops in immunocompromised patients such as HIV-positive patients and transplant recipients. Patients with a prior history of hematopoietic stem cell transplantation (HSCT) have tendency to develop generalized verrucosis. We report an extraordinary case of disseminated epidermodysplasia verruciformis seen in a 7-year-old boy diagnosed with severe combined immunodeficiency syndrome who had undergone HSCT. He had plane, brown papules involving his face, forearms, neck, anterior chest, nape, back, and knees. Cutaneous biopsy showed typical characteristic findings of EV: large cells with gray-blue cytoplasm and keratohyaline granules of different sizes in the granular and spinous layers. Herein, we present an unusual case of disseminated EV in a HSCT patient with typical histopathologic findings and treatment options.