Flat Warts (Verrucae Planae) Confined to the Pigment of a Tattoo: A Rare Tattoo-associated Complication.

Tattoos are a form of decorative body art in which pigment dyes of different colors are inoculated into the skin. It is estimated that 15-25% of general population has one or more tattoos (1), and the reasons for the popularity of this procedure may include greater social acceptance, aesthetic appeal, or perhaps the option of using laser removal techniques to eliminate unwanted tattoos. Even though modern professional tattoos are usually performed in sterile conditions, complications still occur, and with increasing numbers of people getting tattoos, the incidence of tattoo-associated side-effects presenting to dermatologists, which may be as high as 2%, is likely to increase (2). Herein we present a case of a 43-year-old male patient with multiple HPV-associated flat warts (verrucae planae) confined to the black pigment of a tattoo done 15 years ago. A 43-year-old patient presented to our clinic due to eczema on the trunk. However, during skin examination, we observed asymptomatic verrucous papules confined to the black ink of a tattoo done 15 years ago on the lateral side of his right lower leg (Figure 1a). Clinical examination showed multiple, discrete, skin-colored, verrucous papules disseminated exclusively within the lines of the black-colored tattoo. Full skin examination did not reveal any similar lesions anywhere else on the body. Dermoscopically, papules showed a discretely papillomatous surface and sharp borders (Figure 1b). The patient had another black tattoo on his trunk, in which no similar lesions were found. All his tattoos had been done more than 15 years ago in a professional tattoo salon and with no previous history of cutaneous lesions within tattoos. The patient had no other medical conditions and was not taking any medications. Additionally, no history of warts or other HPV-related lesions of the skin or mucosal membranes could be established. A biopsy of an individual papule was taken and sent for a histopathological analysis, which subsequently showed hyperkeratotic, orthokeratotic, and parakeratotic acanthotic epidermis with hypergranulosis and rare cells with perinuclear halo indicative of koilocytes (Figure 3b). Immunohistochemical analysis showed negative reaction for p16 and p53, while Ki67 was positive only in rare basal and suprabasal cells. These findings were indicative of low-risk HPV, and the diagnosis of HPV-induced verruca plana was ultimately established. The patient was then successfully treated with cautious curettage of the lesions, leaving no scars. Due to the growing popularity of tattoos, especially among younger populations, it is necessary to emphasize the possibility of various tattoo-related side-effects that can still occur due to improper preparation of the tattoo location, contamination of ink products, improperly sterilized instruments, or due to insufficient personal hygiene following tattooing (3). In the past, tattoo-associated infections were significantly more frequent, with the highest prevalence of Staphylococcus and Streptococcus infections causing impetigo, folliculitis, cellulitis, erysipelas, or sepsis (2), but recent improvement and efforts in using sterile techniques in tattooing has led to a significant drop in the number of tattoo-related infections. In this short report, we present a case of a different and a relatively rare type of tattoo-associated infection - flat warts i.e., verrucae planae. Flat warts are usually caused by HPV-3, -6B, -10, -28, and -49. Typical predilection sites are the face, dorsal sides of the hands or feet, arms, and legs, and they usually appear as skin-colored, pink, or brown, flat-topped discrete papules. It is believed that HPV can be inoculated through contaminated ink, instruments, the artist's saliva, or that it may be a pre-existing unnoticed wart in the tattooed area (4-6). The latency period between tattooing and HPV infection can range from several months to 10 years, with a mean period of 5 years (3). This may suggest that the immune system can control the infection for some time, and that some form of immune suppression may result in the development of a clinical disease. In our case, the latency period could not be established due to the patient's unawareness of the lesions, and no potential trigger could be identified. The occurrence of lesions on only one of the patient's tattoos as well as their confinement to the black pigmented ink may indicate a correlation to this specific pigment. Ramey et al. (6) conducted a study in which they assessed the localization of warts in differently colored tattoos. The results showed that black ink tattoos had a seven times higher risk of developing warts when compared with colored ink. At first it was thought that this was due to HPV inoculation via contaminated instruments, ink, or autoinoculation of the patient's own warts, but some evidence indicates that it is unlikely for HPV to survive in ink and that if the warts were inoculated they would occur equally in all ink colors. A different theory by Ruocco et al. (7) explains this phenomenon through an "immunocompromised district" mechanism, in which polycyclic aromatic hydrocarbons found in black ink produce reactive oxygen species (ROS) that can damage cellular structures and consequently increase the risk of a variety of infections, including HPV. Moreover, black ink contains almost pure nanoparticles, which are associated with greater ROS production than the larger particles found in colored ink (7,8). There are several treatment options for verrucae planae, such as liquid nitrogen cryotherapy, topical 5% fluorouracil, topical 5% imiquimod, 0.025-0.050% tretinoin, 10% salicylic acid, or 10-30% glycolic acid. These treatments have differing success rates. Destructive modalities, such as surgical excision, curetting, or laser ablation may significantly damage the tattoo and cause scarring, and are thus not regularly performed. It's necessary to emphasize that despite today's sterile methods of tattooing, complications may still occur and medical professionals, namely dermatologists, should be aware of them. A person who wishes to get a tattoo should be advised to visit a licensed tattoo artist at a licensed tattoo parlour only. Patients with pre-existing dermatoses characterized by an isomorphic phenomenon, such as psoriasis or lichen planus, are particularly prone to developing a tattoo-associated adverse reaction, and those with severe dermatoses should be advised to avoid tattooing. Additionally, people with a previous history of warts should be aware of the possibility of warts occurrence, even years or decades after tattooing. Even though most of tattoo-related side effects are merely inconveniences, there is a potential for serious complications and patients should be advised as such.

Human papillomavirus in the setting of immunodeficiency: Pathogenesis and the emergence of next-generation therapies to reduce the high associated cancer risk.

Human papillomavirus (HPV), a common sexually transmitted virus infecting mucosal or cutaneous stratified epithelia, is implicated in the rising of associated cancers worldwide. While HPV infection can be cleared by an adequate immune response, immunocompromised individuals can develop persistent, treatment-refractory, and progressive disease. Primary immunodeficiencies (PIDs) associated with HPV-related disease include inborn errors of GATA, EVER1/2, and CXCR4 mutations, resulting in defective cellular function. People living with secondary immunodeficiency (e.g. solid-organ transplants recipients of immunosuppression) and acquired immunodeficiency (e.g. concurrent human immunodeficiency virus (HIV) infection) are also at significant risk of HPV-related disease. Immunocompromised people are highly susceptible to the development of cutaneous and mucosal warts, and cervical, anogenital and oropharyngeal carcinomas. The specific mechanisms underlying high-risk HPV-driven cancer development in immunocompromised hosts are not well understood. Current treatments for HPV-related cancers include surgery with adjuvant chemotherapy and/or radiotherapy, with clinical trials underway to investigate the use of anti-PD-1 therapy. In the setting of HIV co-infection, persistent high-grade anal intraepithelial neoplasia can occur despite suppressive antiretroviral therapy, resulting in an ongoing risk for transformation to overt malignancy. Although therapeutic vaccines against HPV are under development, the efficacy of these in the setting of PID, secondary- or acquired- immunodeficiencies remains unclear. RNA-based therapeutic targeting of the HPV genome or mRNA transcript has become a promising next-generation therapeutic avenue. In this review, we summarise the current understanding of HPV pathogenesis, immune evasion, and malignant transformation, with a focus on key PIDs, secondary immunodeficiencies, and HIV infection. Current management and vaccine regimes are outlined in relation to HPV-driven cancer, and specifically, the need for more effective therapeutic strategies for immunocompromised hosts. The recent advances in RNA-based gene targeting including CRISPR and short interfering RNA (siRNA), and the potential application to HPV infection are of great interest. An increased understanding of both the dysregulated immune responses in immunocompromised hosts and of viral persistence is essential for the design of next-generation therapies to eliminate HPV persistence and cancer development in the most at-risk populations.

Iatrogenic cutaneous graft versus host disease.

A 65-year-old man with acute myeloid leukemia 6 was treated by bone marrow allograft, developed a systemic classic chronic graft versus host disease with hepatic, rheumatologic, ophthalmic, and muco-cutaneous involvement. He received systemic corticosteroid, ruxolitinib and extracorporeal photopheresis which resulted in complete remission. During follow-up the patient presented with viral cutaneous warts on his neck and submandibular area. After various subsequent topical treatments, he developed localized cutaneous GVHD without any general GVHD reactivation symptoms. To the best of our knowledge, there has been no description in the literature of a graft versus host disease developing after local immunomodulatory or cytotoxic treatments. Topical therapies are commonly used by dermatologists for superficial skin cancers and some viral skin lesions, in high risk populations such as organ transplant patients with regular follow-up.Practitioners should be made aware of a possible localized cutaneous GVHD reactivation induced by Koebner phenomenon after local therapy.

Vulvar and perineal verrucous changes complicating hidradenitis suppurativa after wide excision: a case and literature review.

Poorly controlled and long-standing hidradenitis suppurativa (HS) increases the risk of squamous cell carcinoma (SCC). We report a 54-year-old woman with an over 20-year history of HS, who had previously undergone wide perineal excision with secondary intention healing and presented with a painful verrucous vulvar plaque and proximal non-healing perineal wound. The patient had four perineal scouting biopsies performed and excisional biopsy with no evidence of high-grade dysplasia or carcinoma on histology. Chromogenic in situ hybridization was negative for HPV 16 and 18 mRNA; the patient's HIV and HSV PCR were also negative. Our patient was treated with interferon alfa-2b with notable clinical improvement. There is currently no standardized stepwise approach to monitoring verrucous lesions in HS patients with significant risk factors for SCC. Our report highlights a vigilant approach to monitoring. If scouting biopsies are negative, complete testing for high risk HPV strains (HPV 16 and 18) is warranted. If negative, we recommend follow up every 6 months with no further biopsies except if overt clinical changes are observed. We also recommend treatment of verrucous changes to decrease risk of possible malignant conversion. Interferon alfa-2b was effective in decreasing the verrucous lesion burden in our patient and may be considered.

Intact B-Cell Signaling and Function With Host B-Cells 47 Years After Transplantation for X-SCID.

Introduction: Severe Combined Immunodeficiency (SCID) is a life-threatening immunodeficiency caused by several pathogenic genetic variants, and it is characterized by profound defects in T-cell numbers and immune function. First performed in the late 1960's, hematopoietic stem cell transplantation remains the standard treatment for most cases of SCID. There is a growing number of post-transplant SCID patients, and it is imperative to assess the long-term outcomes of these patients. We have reported here the longest follow-up of a post-transplant SCID patient who, to our knowledge, bears the first gamma chain (γc) variant to show intact IL-21 signaling. Case Presentation: The patient presented at 5 months of age with recurrent thrush and Pneumocystis jiroveci pneumonia. In 1971, at the age of 11 months, he received an unconditioned, matched, related donor transplant comprising whole, unprocessed bone marrow. He is now 48 years old without significant illness and has never required immunoglobulin replacement. He exhibits T-dependent vaccine responses. He does suffer from chronic warts and bacterial infections that have worsened in recent years. We confirmed a known pathogenic variant in the IL2RG gene showing a hemizygous variant NM_000206.2:c.675C>A, resulting in p.Ser225Arg. His chimerism studies revealed donor T cells, host B cells, host myeloid cells, and mixed NK cells. Lymphocyte enumeration revealed normal numbers and distribution of B cells. The host B cells carry the pathogenic variant in IL2RG, but, when stimulated with IL-21, they demonstrated intact, γc-dependent signaling. Conclusions: Even with host B cells, reconstitution with donor T cells can be sufficient to allow over four decades of survival when B-cell function is intact. Our case demonstrates that satisfactory B-cell function can arise as a consequence of both intact IL-21 signaling due to a hypomorphic γc variant, and close HLA matching with the donor to allow for effective T-cell help.

Verruciform xanthoma in recessive dystrophic epidermolysis bullosa and keratitis-ichthyosis-deafness syndrome: Report of two cases and a review of the literature.

Verruciform xanthoma is a benign, wart-like lesion that can clinically mimic squamous cell carcinoma. We describe two teenage patients with severe genodermatoses, recessive dystrophic epidermolysis bullosa (RDEB), and keratitis-ichthyosis-deafness (KID) syndrome, respectively, each found to have plaques suspicious for malignancy, later demonstrated on histopathologic examination to be verruciform xanthoma. We discuss the connection between these severe genodermatoses and the suspected pathophysiology of verruciform xanthoma. In addition, we highlight the importance of recognizing verruciform xanthoma as a clinical mimicker of squamous cell carcinoma, for which patients with RDEB and KID syndrome are at increased risk.

WHIM Syndrome: from Pathogenesis Towards Personalized Medicine and Cure.

WHIM syndrome is a rare combined primary immunodeficiency disease named by acronym for the diagnostic tetrad of warts, hypogammaglobulinemia, infections, and myelokathexis. Myelokathexis is a unique form of non-cyclic severe congenital neutropenia caused by accumulation of mature and degenerating neutrophils in the bone marrow; monocytopenia and lymphopenia, especially B lymphopenia, also commonly occur. WHIM syndrome is usually caused by autosomal dominant mutations in the G protein-coupled chemokine receptor CXCR4 that impair desensitization, resulting in enhanced and prolonged G protein- and ß-arrestin-dependent responses. Accordingly, CXCR4 antagonists have shown promise as mechanism-based treatments in phase 1 clinical trials. This review is based on analysis of all 105 published cases of WHIM syndrome and covers current concepts, recent advances, unresolved enigmas and controversies, and promising future research directions.

Surgical removal for khat inducible verruca vulgaris lesion of the oral mucosa.

The harmful effects of khat chewing on the oral mucosa membrane are still uncertain. Verruca vulgaris (common warts) is a benign lesion of skin and mucous membranes and can be caused by human papillomavirus. The lesions are typically self-limited but may vary in size and number. The occurrence on the floor of mouth is extremely rare. To the best of our knowledge, there are few number of oral lesions reported in connection with khat users. This case report shows that the chronic khat chewing has contributed to the development of verruca vulgaris warts that were confined to the chewing side of the mouth. A rare case of verruca vulgaris of the floor of mouth occurring in a 27-year-old Yamani male is presented with a discussion on etiopathogenesis and the treatment methods. Verruca vulgaris must be remembered in the differential diagnosis of the floor of mouth lesions, and surgical treatment may provide satisfactory outcomes.

Warts and all: Fingolimod and unusual HPV-associated lesions.

BACKGROUND: Fingolimod is used to reduce relapse rates in relapsing-remitting multiple sclerosis (MS). It is a sphingosine 1-phosphate (S1P) analogue having antagonistic effects on S1P receptors. Its immunosuppressive effect is due to reduced circulating lymphocyte numbers, and it may also be associated with impaired intrinsic cancer surveillance. Fingolimod side effects include increased rates and severity of viral infections particularly varicella zoster. METHODS: We present five cases of chronic and treatment refractory warts associated with fingolimod therapy. RESULTS: Each of the five cases presenting with chronic warts while receiving fingolimod therapy had prolonged periods of lymphopenia and improvements were seen following dose reduction or cessation of fingolimod. CONCLUSION: Cutaneous warts are associated with human papilloma virus (HPV) infection, suggesting an increased risk of other HPV-driven conditions such as cervical cancer following fingolimod administration. HPV viruses are responsible for approximately 90% of cervical cancers as well as a significant portion of anogenital cancers and have a high prevalence in sexually active adults. Given the reduced immune response to viral infections and potential impaired cancer surveillance in those receiving fingolimod, HPV vaccination and frequent assessment for the development of HPV-associated malignancies are recommended.

Adaptive Immunodeficiency in WHIM Syndrome.

Cysteine-X-cysteine chemokine receptor 4 (CXCR4) is a broadly expressed and multifunctional G protein-coupled chemokine receptor critical for organogenesis, hematopoiesis, and antimicrobial host defense. In the hematopoietic system, the binding of CXCR4 to its cognate chemokine ligand, CXCL12, mediates leukocyte trafficking, distribution, survival, activation, and proliferation. Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a rare, autosomal dominant, combined immunodeficiency disorder caused by mutations in the C-terminus of CXCR4 that prevent receptor downregulation and therefore result in pathologically increased signaling. The "M" in the acronym WHIM refers to myelokathexis, the retention of neutrophils in the bone marrow resulting in neutropenia, which explains in part the increased susceptibility to bacterial infection. However, WHIM patients also present with B and T lymphopenia, which may explain the susceptibility to human papillomavirus (HPV), the cause of warts. The impact of WHIM mutations on lymphocytes and adaptive immunity has received less attention than myelokathexis and is the focus of this review.

Allogeneic hematopoietic cell transplantation in patients with GATA2 deficiency-a case report and comprehensive review of the literature.

Recently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients with GATA2 deficiency, but once infectious symptoms occur or MDS/AML arises, survival declines significantly. Allogeneic hematopoietic cell transplantation (HCT) currently provides the only curative treatment option for both MDS/AML and dysfunctional immunity with life-threatening opportunistic infections. Strategies regarding timing of allogeneic HCT, antimicrobial prophylaxis and treatment, intensity of the preparative regimen, and optimal donor and graft source have not been clearly defined due to the rarity of the disease. Here, we provide a comprehensive analysis of the available literature and published case reports on the use of allogeneic HCT in patients with GATA2 deficiency. In addition, a case of a young woman with GATA2 deficiency, who developed an immune reconstitution inflammatory syndrome in her mycobacterial skin lesions post allogeneic HCT is presented and illustrates distinct problems encountered in this disease context.

The Ring Verruca Plantaris in Cantharidin Use A Case Report.

Verrucae (warts) are the most common viral infections of the skin, affecting 7% to 10% of the general population. Typically caused by human papillomavirus type 1, plantar warts manifest as benign proliferation of the epithelial cells on the feet. It has been cited that up to one-third of nongenital warts become recalcitrant, and biopsy is often required to confirm diagnosis and direct appropriate treatment. These treatments can vary from various types of oral medications, acids, ablative modalities, and injections. In this article, we present a case of a recalcitrant plantar wart that appeared to circumferentially spread from the initial site after first-line treatment and presumed resolution with the product cantharidin. The development of ring warts is a known complication associated with cantharidin use, with little described rationale to the presentation.

Verruca vulgaris of the buccal mucosa: A case report.

Oral verruca vulgaris is caused by human papillomavirus (HPV) infection. Verruca vulgaris most frequently occurs on the fingers, toes, soles, and dorsal surfaces of hands and is mostly asymptomatic. Varieties of verrucous and papillary lesions affect the skin as well as oral mucosa which may be either benign or reactive. Common wart is one of the most commonly observed skin growths and a lesion of childhood. Intraoral warts can occur at any age with equal incidence in both genders but are most commonly seen in the third to fifth decade. It is found commonly on the palate followed by lip, tongue, buccal mucosa, and rarely seen on gingiva. Surgical excision with adequate margins is the treatment of choice.

How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome.

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is a genetic disease characterized by neutropenia, lymphopenia, susceptibility to infections, and myelokathexis, which describes degenerative changes of mature neutrophils and hyperplasia of bone marrow myeloid cells. Some patients present with hypogammaglobulinemia and/or refractory warts of skin and genitalia. Congenital cardiac defects constitute uncommon manifestations of the disease. The disorder, which is inherited as an autosomal dominant trait, is caused by heterozygous mutations of the chemokine receptor CXCR4. These mutations lead to an increased sensitivity of neutrophils and lymphocytes to the unique ligand CXCL12 and to an increased accumulation of mature neutrophils in the bone marrow. Despite greatly improved knowledge of the disease, therapeutic choices are insufficient to prevent some of the disease outcomes, such as development of bronchiectasis, anogenital dysplasia, or invasive cancer. The available therapeutic measures aimed at preventing the risk for infection in WHIM patients are discussed. We critically evaluate the diagnostic criteria of WHIM syndrome, particularly when WHIM syndrome should be suspected in patients with congenital neutropenia and lymphopenia despite the absence of hypogammaglobulinemia and/or warts. Finally, we discuss recent results of trials evaluating plerixafor, a selective antagonist of CXCR4, as a mechanism-oriented strategy for treatment of WHIM patients.