Unrecognized Bowen's disease in previously treated condylomata acuminata: indication of a common etiology?

Bowen's disease (BD) is an intraepidermal squamous cell carcinoma (SCC) with the capacity to become invasive SCC giving rise to distant metastasis. In rare cases it can be associated with human papillomavirus (HPV) infection, specifically with HPV types 16, 18, 31, 32, and 34. Here we report a case of an immunocompetent white male, age 37, with an erythematous, irregularly-shaped patch in his suprapubic region, appearing 1 year after treatment for condylomata acuminata with cryotherapy and podophyllin in the same area. At the time of clinically active disease, a urethral smear was positive for high-risk HPV types. The lesion was considered a scar by several physicians because it emerged in an area of previous postinflammatory hyperpigmentation. The aim of this report is to raise awareness of the emerging causative association between anogenital HPV infection and the development of BD, which was the possible etiological agent in the case of the patient presented here. Hereby we also advocate primary preventive measures in terms of safe sexual habits and HPV vaccination.

Human papillomavirus is more frequently detected in the pelvic than non-pelvic area in patients with squamous cell carcinoma in situ (Bowen's disease).

BACKGROUND: The detection rate of human papillomavirus (HPV) in Bowen's disease (BD) varies greatly. OBJECTIVES: To detect HPV DNA in BD samples using next-generation sequencing (NGS) and compare HPV detection rates between pelvic and non-pelvic BD. MATERIALS AND METHODS: We evaluated 99 patients with BD in our institution. DNA was extracted from formalin-fixed and paraffin embedded (FFPE) tissue blocks. The presence of HPV DNA material was detected using special kit-based NGS technology. Clinical characteristics and HPV detection rates were then compared between pelvic and non-pelvic BD samples. RESULTS: HPV was detected in 26 (26.3%) BD samples. A total of 10 types of α-HPV was detected: HPV 16, 53, 31, 58, 66, 26, 27, 57, 45, and 72. The most common HPV type was 16 (12.1%). Only two types (27 and 57) were frequently classified as cutaneous type, and the rest were mucosal types. The HPV detection rate was significantly higher in pelvic BD (45.2%) compared to non-pelvic BD (17.6%). CONCLUSION: The present study suggests that sexually transmitted mucosal α-HPV plays a significant role in the pathogenesis of BD, especially in the pelvic region.

Subclonal Evolution of Cancer-Related Gene Mutations in p53 Immunopositive Patches in Human Skin.

Normal sun-exposed skin contains numerous epidermal patches that stain positive for p53 protein (p53 immunopositive patches, PIPs), which are considered potential early precursors of skin cancer. Although the TP53 gene is mutated in many PIPs, it is unclear whether PIPs contain any other cancer-related mutations. Here we report that PIPs, predominantly <3,000 p53 immunopositive cells in size, within normal chronically exposed skin contain mutations in multiple genes that are mutated in cutaneous squamous cell cancers. These mutations in the PIPs were not detected within the non-PIP epidermis of corresponding normal chronically exposed skin. Although some of these genetic alterations are clonal in the PIPs, many of the mutations are subclonal within these lesions. Similar mutations are seen in later precancers (actinic keratoses and Bowen's disease). Our results demonstrate that PIPs in chronically exposed skin contain multiple mutations in cancer-related genes. In addition, the results indicate that the clonal evolution of mutations that are seen within later precancerous lesions and in established malignancy can also occur in PIPs within normal human skin.

Aminoleveulinate photodynamic therapy (ALA-PDT) for Bowen's disease in a SLE patient: Case report and literature review.

We reported a rare case of topical 5-aminolevulinic acid (ALA)-photodynamic therapy (PDT) in the treatment of a systemic lupus erythematosus (SLE) patient with lower limb multiple Bowen's disease (BD). At the end of the treatment, an excellent clinical response was observed and no recurrence of rash after 2 months of treatment. The recovery time was prolonged only after the first treatment, however, no photosensitive phenomena were observed during and after the treatment. This is the first report to describe ALA-PDT for patient-confirmed photosensitivity in an Asian patient. Whether PDT is contraindicated for SLE remains to be discussed, although our findings show that PDT can be used as an alternative therapy for SLE patients with BD who cannot tolerate surgery.

Pathogenesis of abdominal pain in bowel obstruction: role of mechanical stress-induced upregulation of nerve growth factor in gut smooth muscle cells.

Abdominal pain is one of the major symptoms in bowel obstruction (BO); its cellular mechanisms remain incompletely understood. We tested the hypothesis that mechanical stress in obstruction upregulates expression of nociception mediator nerve growth factor (NGF) in gut smooth muscle cells (SMCs), and NGF sensitizes primary sensory nerve to contribute to pain in BO. Partial colon obstruction was induced with a silicon band implanted in the distal bowel of Sprague-Dawley rats. Colon-projecting sensory neurons in the dorsal root ganglia (T13 to L2) were identified for patch-clamp and gene expression studies. Referred visceral sensitivity was assessed by measuring withdrawal response to stimulation by von Frey filaments in the lower abdomen. Membrane excitability of colon-projecting dorsal root ganglia neurons was significantly enhanced, and the withdrawal response to von Frey filament stimulation markedly increased in BO rats. The expression of NGF mRNA and protein was increased in a time-dependent manner (day 1-day 7) in colonic SMC but not in mucosa/submucosa of the obstructed colon. Mechanical stretch in vitro caused robust NGF mRNA and protein expression in colonic SMC. Treatment with anti-NGF antibody attenuated colon neuron hyperexcitability and referred hypersensitivity in BO rats. Obstruction led to significant increases of tetrodotoxin-resistant Na currents and mRNA expression of Nav1.8 but not Nav1.6 and Nav1.7 in colon neurons; these changes were abolished by anti-NGF treatment. In conclusion, mechanical stress-induced upregulation of NGF in colon SMC underlies the visceral hypersensitivity in BO through increased gene expression and activity of tetrodotoxin-resistant Na channels in sensory neurons.

Bowel Management and Quality of Life in Children With Spina Bifida in South Korea.

Bowel management is a concern in patients with spina bifida. We evaluated the status of bowel management in children with spina bifida (SB) and the effects on quality of life (QoL) of children and their caregivers. Data were collected from 173 children with SB between January and June 2011, whose bowel management status and QoL were assessed using a self-administered questionnaire. Of the 173 children, 38 (22.0%) reported normal defecation, 73 (42.2%) reported constipation only, and 62 (35.8%) reported fecal incontinence with/without constipation. For defecation, 59 children (34.1%) used digital stimulation or manual extraction, 28 (16.2%) used suppositories or enemas, 35 (20.3%) used laxatives, 4 (2.3%) used an antegrade continence enema, and 3 (1.7%) used transanal irrigation. There were significant differences in QoL, depending on defecation symptoms. Children with fecal incontinence and their caregivers had difficulties in travel and socialization (p < .0001), caregivers' emotions (p < .0001), family relationships (p < .0001), and finances (p < .0001). Constipation and fecal incontinence affect QoL of children with SB and their caregivers. Therefore, more attention should be paid to bowel problems and help should be provided to children and their caregivers to improve QoL.

An Interaction between Arsenic-Induced Epigenetic Modification and Inflammatory Promotion in a Skin Equivalent during Arsenic Carcinogenesis.

Animal studies have shown that chemical carcinogenesis consists of a three-stage process: initiation, promotion, and progression. However, because of the lack of a suitable tissue model, the molecular mechanisms of cell-cell interactions involved in those processes remain unclear. We have established a human intraepidermal carcinoma skin equivalent with organotypic culture-consisting of keratinocytes, fibroblasts, and peripheral blood mononuclear cells - induced by arsenic treatment. This SE shows the pathognomonic characteristics of arsenic-induced Bowen's disease, including acanthosis, dysplasia, and dyskeratosis. Using this SE model, we showed that arsenic initiated SUV39H2-mediated epigenetic modification of E2F1, which induced centrosome amplification in keratinocytes in 2 days; this, however, led to caspase-8-mediated apoptosis in 10 days. In parallel, arsenic stimulated tumor necrosis factor-α release mainly from peripheral blood mononuclear cells. Tumor necrosis factor-α triggered anti-apoptotic signals via FLIP-associated caspase-8 inactivation in arsenic-treated keratinocytes, which in turn contributed to cell survival and aneuploidy. The interaction between arsenic-induced epigenetic modification and inflammatory promotion resulted in the development of the pathognomonic features of arsenic-induced Bowen's disease in this model.

Giant extragenital Bowen's disease.

Giant extragenital forms of Morbus Bowen are extremely rare. The already described cases in the word literature are most commonly with periungual localization, as well as located on the foot and neck area. The clinical manifestation is presented most commonly by non-specific erythematous to erythematous-squamous plaques or papules, which is confusing to the clinician. From the pathogenic point of view, it is important to be confirmed or rejected the presence of human papilloma viruses (HPVs) in each case of affected patient, as this information is mandatory in respect to the adequate selection of the subsequent regimen. If HPVs are detected, systemic antiviral therapy could be initiated to reduce the size of the lesions before subsequent surgical eradication. A postoperative prevention through vaccination could be also considered additionally. In cases of HPV-negative giant extragenital forms of Morbus Bowen (as in the described patient), the focus should be on local immunomodulation by substances such as imiquimod, which reduce the size of the lesions, thereby creating optimal opportunities for their future surgical eradication. Other possible options described in the literature include topical application of 5-fluorouracil, photodynamic therapy, cryotherapy, and laser therapy (carbon dioxide laser). The choice of the most appropriate regimen should have been an individual decision of the clinician, considering also the location and the extent of the lesion.

[Risk factors of non melanoma skin cancers in kidney transplant patients]. / Czynniki ryzyka rozwoju nieczerniakowych raków skóry u chorych po przeszczepieniu nerki.

UNLABELLED: Non melanoma skin cancers (NMSC) represent a major challenge within the ever growing group of different organs recipients. The aim of the study was to evaluate risk factors influencing on frequency appearance of NMSC in patients after kidney transplantation. The clinical dermatological examination was performed in 486 patients after kidney transplantation consisted of 296 man (60.9%) and 190 woman (30.1%) in the mean age 46.1 +/- 13.1 (18-74 years) with median time after transplantation 74.3 +/- 52.1 months. Most of them (80.7%) before transplantation were treated by maintenance hemodialysis. Patients after kidney transplantation were checked by dermatologist for all skin abnormalities based on iniciated skin cancers screening program. All discovered abnormalities were described, their type, size, localization and results of histopathological examination were collected. The obtained results were analyzed based on t-Student's, Mann-Whitney's, chi-square and Fisher tests. Out of 486 studied patients, 53 NMSC were diagnosed in 25 kidney recipients including 39 basal cell carcinoma (BCC), 13 squamous cell carcinoma (SCC) and 1 Bowen's disease. The proportion of BCC to SCC was 2.79. NMSC occurred more often on sun skin exposure area, especially on the face. Almost all (96.2%) of the cancers were diagnosed in patients older than 50 years of age. Patients with NMSC comparing with those without were significantly older (52.8 +/- 7.8 vs. 41.0 +/- 7.8; p < 0.0001), have longer post-transplant period and have more frequent positive anamnesis of this cancer. There was no significant relationship between NMSC appearance and sex, cause of kidney failure, HLA mismatch, blood group as well as Rh factor. CONCLUSIONS: Older age of patients while transplantation, longer time of immunosuppressive therapy and previous NMSC are independent predictors of new skin cancers appearance.

Neuroblastoma with symptomatic epidural compression in the infant: the AIEOP experience.

BACKGROUND: Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. PATIENTS AND METHODS: Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. RESULTS: Median age at initial SEC was 104 days (IQR 47-234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7-34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P = 0.039) and grade 3 motor deficit (P = 0.084). CONCLUSIONS: Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted.

Ischemic bowel disease and risk of stroke: a one-year follow-up study.

BACKGROUND: Ischemic bowel disease and stroke have been noted to have shared pathomechanisms. However, data regarding the stroke occurrence following ischemic bowel disease are still lacking. AIM: The aim of this study is to explore the risk of stroke in patients with ischemic bowel disease during a one-year follow-up period in Taiwan. METHODS: Data used in this study were retrieved from the 'Longitudinal Health Insurance Database 2000. Five hundred sixty-nine patients hospitalized with ischemic bowel disease were included as the study group, and 3414 subjects, matched by age and gender, were randomly extracted as a comparison group. Cox proportional hazards regression analysis was performed to test the relationship of ischemic bowel disease and subsequent stroke during the one-year follow-up period. RESULTS: The incidence rate of stroke among the sampled subjects during the 30-day, 90-day, and 365-day follow-up period was 1·24, 0·76, and 0·43 per 10 person-years. The adjusted hazard ratio for stroke for those patients with ischemic bowel disease within 30-, 90-, and 365-day follow-up periods was found to be 3·71 (95% confidence interval = 1·89-7·27), 2·11 (95% confidence interval = 1·22-3·66), and 1·70 (95% confidence interval = 1·14-2·52) times that of matched comparisons, respectively. The adjusted hazard ratio of ischemic stroke for patients with ischemic bowel disease was found to be 5·29 during the 30-day follow-up period than comparisons. CONCLUSIONS: We found ischemic bowel disease to be significantly associated with stroke occurrence.

Expression of hypoxia-inducible factor-1α, vascular endothelial growth factor and prolyl hydroxylase domain protein 2 in cutaneous squamous cell carcinoma and precursor lesions and their relationship with histological stages and clinical features.

The hypoxia-inducible factor-1 (HIF-1α) pathway is associated with tumor growth, angiogenesis and metastasis in various carcinomas. Little is known regarding the role of the HIF-1α signaling pathway in cutaneous squamous cell carcinoma (SCC). We investigated the expression of HIF-1α, vascular endothelial growth factor (VEGF) and the HIF negative regulator, prolyl hydroxylase domain protein 2 (PHD2), in cutaneous SCC, Bowen's disease, seborrheic keratosis (SK) and normal skin by immunohistochemistry and in situ hybridization. Additionally, we explored the relationships between these factors and the clinical and histological characteristics of each disease. Our study indicated that the expression of HIF-1α and VEGF was significantly higher (P < 0.05) in cutaneous SCC than in Bowen's disease, SK or normal skin. In contrast, PHD2 showed significantly higher expression in normal skin compared with SK, Bowen's disease and cutaneous SCC (P < 0.05). Grade II-IV cutaneous SCC had higher expression levels of nuclear HIF-1α and cytoplasm VEGF protein but less nuclear PHD2 protein than grade Ι cutaneous SCC (P < 0.05). Overexpression of HIF-1α and VEGF, as well as the decreased expression of PHD2, may play important roles in the development of cutaneous SCC.

Malignant change in seborrhoeic keratoses in a region with high solar ultraviolet levels.

Regions with high solar UV levels and high skin cancer rates may experience a greater incidence of malignancy in association with seborrhoeic keratoses (SebK) than in low UV regions. Previous reports have indicated that basal cell carcinoma is the most common neoplasm with reported rates of up to 4 per cent of excised SebK. The rates of such compound lesions occurring in our practice were reviewed, indicating that Bowen's disease was the most frequently observed neoplasm with a rate of 7 per cent. In total, 10 per cent of all excised specimens showed either frank malignancy or some degree of atypia.

Analysis of the 3'UTR of the prostaglandin synthetase-2 (PTGS-2/COX-2) gene in non-melanoma skin cancer after organ transplantation.

To define the potential involvement of polymorphisms in the 3'untranslated region (3'UTR) of the prostaglandin synthetase-2 (PTGS-2) gene to non-melanoma skin cancer (NMSC) predisposition after transplantation, we screened for genetic variant, relevant parts of this region. It contains binding sites for trans-acting factors, an alternative polyadenylation site and putative target sequences for miRNAs. Variant +8473T>C did not appear to play a functional role in the regulation of gene expression in human keratinocyte-transfected cells. In addition to the well-known +8473T>C, we identified four polymorphisms: +8293G>C, +10259T>G, +10267G>A and +10335G>A. No allele frequency differences were observed between cases and controls neither for +8473T>C nor for any of the identified polymorphisms, suggesting that polymorphisms in the 3'UTR of the PTGS2 gene are rare and unlikely to represent risk factor for NMSC after transplantation.

Multiple Bowen's disease in a patient with a history of possible arsenic exposure: a case report.

A 81-year-old man with a patch of scaly erythema on his scrotum visited Hiratsuka Kyosai Hospital in June 2006. Reddish, scaly plaques, which were untreated, were present on his back and lower legs since 1999. Pathological examination of the lesions on the scrotum revealed Bowen's disease; therefore he was referred to our clinic for further treatment. During his visit Tokai University Hospital, irregularly bordered scaly erythematous patches were observed on his back, left arm, right knee, and right foot, sizing from 2 to 4 cm in diameter. He was treated with phenol and liquid nitrogen cryotherapy; however, he dropped out of clinic after receiving treatment for a year. At this point, most lesions were cured and only scars remained. In June 2009, he revisited Tokai University Hospital, and this time, multiple scaly erythematous patches were noted on his back and both the arms and legs. The results of the biopsies of 4 lesions obtained from the back, right arm, right knee, and the right foot led to the diagnosis of multiple Bowens' disease. During the inquiry, we learned that since birth, he has resided in Hiratsuka City and had often used water from wells. We researched the possibilities of water and soil contaminations in the Hiratsuka area.

Pigmented Bowen disease arising in pigmented reticulated seborrheic keratosis.

A 76-year-old man consulted to our hospital complaining of a black tumor of the temporal head. The tumor was nodular mass measuring 1 × 1 × 0.6 cm and black. A clinical diagnosis of basal cell carcinoma was made, and an excision with wide margins was performed. Histologically, the tumor was symmetrical, with horny keratinization in the center. An aggregate of atypical cells regarded as malignant cells was present in the center. No invasion was recognized. The cells were heavily pigmented. Mitotic figures, individual keratinization, and clumping cells were also recognized. Numerous dendritic melanocytes were recognized in the malignant lesion. Immunohistochemically, strong p53 expression was present in all malignant cells, and the malignant cells showed a high Ki-67 labeling of 60%. They were negative for melanosome and S100 protein and positive for cytokeratins. The periphery of the tumor showed typical features of pigmented reticulated seborrheic keratosis. There were gradual merges between the two lesions. This case suggests that pigmented Bowen disease can arise in pigmented reticulated seborrheic keratosis.

MMP-10 (Stromelysin-2) and MMP-21 in human and murine squamous cell cancer.

The squamous cell cancers (SCC) of renal transplant recipients are more aggressive and metastasize earlier than those of the non-immunocompromised population. Matrix metalloproteinases (MMPs) have a central role in tumor initiation, invasion and metastasis. Our aim was to compare the expression of MMPs-10, -12 and -21 in SCCs from immunosuppressed (IS) and control patients and the contribution of MMPs-10 and -21 to SCC development in the FVB/N-Tg(KRT5-Nfkbia)3Rto mouse line. Immunohistochemical analysis of 25 matched pairs of SCCs, nine of Bowen's disease and timed back skin biopsies of mice with selective inhibition of Rel/NF-kappaB signalling were performed. Semiquantitatively assessed stromal MMP-10 expression was higher (P = 0.009) in the control group when compared with IS patients. Tumor cell-derived MMP-10, -12 and -21 expression did not differ between the groups but stromal fibroblasts of the control SCCs tended to express MMP-21 more abundantly. MMP-10 expression was observed already in Bowen's disease while MMP-21 was absent. MMP-10 and -21 were present in inflammatory or stromal cells in ageing mice while dysplastic keratinocytes and invasive cancer were negative. Our results suggest that MMP-10 may be important in the initial stages of SCC progression and induced in the stroma relating to the general host-response reaction to skin cancer. MMP-21 does not associate with invasion of SCC but may be involved in keratinocyte differentiation.