Delay of endoscopic submucosal dissection-induced gastric ulcer healing by methotrexate.

We report a case of methotrexate (MTX) delaying the healing of an endoscopic submucosal dissection (ESD)-induced gastric ulcer. The patient, who had been taking MTX for rheumatoid arthritis, underwent ESD for early gastric carcinoma. Despite taking vonoprazan after ESD, abdominal pain and anorexia continued, and the gastric ulcer did not heal after the ESD. After discontinuing MTX, the patient's symptoms improved and the ulcer healed. Patients taking MTX require careful follow-up after ESD, considering that ulcers can be difficult to heal. Discontinuation of MTX should be considered if delayed healing of an ulcer is observed.

Histiocytic sarcoma following combination chemotherapy for primary mediastinal germ cell tumor: a diagnostic dilemma.

Histiocytic sarcoma is considered an extremely rare condition. We herein report on a case of histiocytic sarcoma following combination chemotherapy for a primary mediastinal germ cell tumor in a 26-year-old Asian man who visited the General Medicine Department of a hospital with complaints of cough and high fever. Chest computed tomography (CT) imaging revealed a tumor (diameter 10.5 cm) in the anterior mediastinum, with no signs of metastasis, and CT-guided biopsy of the mediastinal tumor revealed the presence of some necrotic cartilages. The patient's serum α-fetoprotein (AFP) level was determined to be high at 160.4 ng/mL and a primary mediastinal non-seminomatous germ cell tumor was suspected, so the patient was referred to the Department of Urology. Despite the presence of severe thrombocytopenia, the patient was treated using a combination of chemotherapy and intermittent transfusion, which was able to normalize his serum AFP level. However, resection of the mediastinal tumor was unsuccessful due to persistent thrombocytopenia and the patient was subsequently transferred to our hospital for further examination and treatment. Despite management by hematologists, the condition of the patient did not improve; although his AFP level remained normal, the tumor increased in size and then metastasized to the liver and spleen. The general condition of the patient deteriorated and he died 9 months after his first visit. The patient was diagnosed with histiocytic sarcoma following a pathological autopsy. Due to the extremely rare incidence of histiocytic sarcoma, this condition should be a differential diagnosis and the appropriate tests must be conducted to give an exact treatment.

Inflammatory Pseudotumor Formation at a Port Site after Robotic Partial Nephrectomy for Renal Cell Carcinoma.

Inflammatory pseudotumors (IPTs) are benign masses arising from nonspecific inflammatory conditions including surgical invasion. We herein report the rare case of an IPT mimicking port-site metastasis in a 69-year-old patient who underwent retroperitoneal robotic partial nephrectomy for stage T1a renal cell carcinoma. Radiological examination performed six months after the surgery revealed the presence of a mass underneath the abdominal wall which coincided with a port site. The tumor was resected by laparoscopic transperitoneal approach, and histological examination led to the diagnosis of an IPT that consists of xanthogranulomatous inflammation. We also discuss the etiology of IPT formation and features distinguishing IPTs from port-site metastasis.

Testicular rhabdomyosarcoma after chemotherapy for metastatic germ cell tumors.

A 36-year-old male was referred to our hospital with left scrotal swelling. Computed tomography revealed a massive tumor in his left scrotum. The tumor extended along the gonadal vein extraperitoneally forming a massive tumor. Pathological examination showed a mixed-type germ cell tumor. Despite several chemotherapeutic treatments, the tumor continued to grow, and the patient died 28 months later after his first presentation at our institution. Autopsy revealed that the tumor comprised rhabdomyosarcoma and mature teratoma. We could not find useful tumor markers to facilitate the diagnosis of rhabdomyosarcoma. However, we recommend rebiopsy or palliative operation as options for re-diagnosis in case of resistant germ cell tumor. Here, we present a case of testicular tumor that exhibited different pathological examination results before and after treatment.

Efficacy of combined prophylactic use of levofloxacin and isepamicin for transrectal prostate needle biopsy: A retrospective single-center study.

PURPOSE: To assess the efficacy of a combined regimen of levofloxacin (LVFX) plus isepamicin (ISP) as prophylaxis for transrectal ultrasound-guided needle biopsy of the prostate (TRUSP-Bx). MATERIALS AND METHODS: Overall, 562 patients undergoing TRUSP-Bx were included in the present study. All patients were administered a single-dose of oral LVFX (500 mg) in the morning and intravenous ISP (400 mg) 60 min before biopsy. All biopsies were performed via TRUSP-Bx with an 18-gauge needle, and 12-core specimens were routinely obtained. Before initiating antibiotic treatment, urine and blood bacterial cultures were tested to determine the causative microorganisms in the patients with acute bacterial prostatitis. RESULTS: Acute bacterial prostatitis developed in three (0.53%) participants. The incidence rates of acute bacterial prostatitis in the low- and high-risk groups were 0.79% and 0.46%, respectively. These patients showed clinical symptoms of acute bacterial prostatitis 12-24 h after their biopsy. Escherichia coli (E. coli) was isolated in the urine or bladder cultures of all of patients. All three isolates were determined to be LVFX-resistant E. coli, although they had good sensitivity to aminoglycosides, cephalosporins, and carbapenems. All patients were administered antibiotic treatment (cephalosporin or carbapenem) immediately and were treated successfully with no evidence of further disease progression. CONCLUSION: Antibiotic prophylaxis with LVFX plus ISP was effective, resulting in a lower incidence of acute bacterial prostatitis after TRUSP-Bx in both low- and high-risk patients.

Etiological role of human papillomavirus infection in the development of penile cancer.

OBJECTIVE: To examine the association between human papillomavirus (HPV) infection and penile cancer among Japanese patients. METHODS: Thirty-four patients with penile cancer were enrolled in this study. DNA was extracted from paraffin-embedded tumor tissue samples, and HPV-DNA tests and genotyping were performed. For all of the samples, in situ hybridization (ISH) was performed to locate HPV-DNA in tumor tissue. Furthermore, expression levels of p16-INK4a, mini-chromosome maintenance protein 7(mcm-7), HPV-L1, and Ki-67 were analyzed using immunohistochemical methods. RESULTS: HPV and high-risk (HR)-HPV were detected in 14 (41.1%; 95% confidence interval (CI) 24.6-57.7%) and 12 (35.2%; 95% CI 19.2-51.4%) cases, respectively. HPV16 was the most frequently detected HPV type. Among the HR-HPV-positive cases, a punctate HR-HPV-DNA signal pattern was detected by ISH in tumor cell nuclei. P16-INK4a was expressed in 66.7% (95% CI 42.8-90.1%) of HR-HPV-positive cases and was significantly more frequent and stronger in HR-HPV-positive cases than in HPV-negative cases. There was no significant difference in the occurrence or distribution of mcm-7 or Ki-67 expression between HPV-positive and HPV-negative cases. HPV-L1 expression was not observed in any of the cases examined. CONCLUSIONS: HPV infection may have had an etiological role in 41% of the examined cases of penile cancer in Japan.

Evaluation of Factors Affecting Metastasis for Renal Cell Carcinoma Based on Current Guidelines in Japan.

BACKGROUND/AIM: To analyze the suitability for metastasis evaluation of each pathologic item on the Fourth Edition of the General Rule for Clinical and Pathologic Studies on Renal Cell Carcinoma in Japan. PATIENTS AND METHODS: We retrospectively examined 457 cases of renal operation after 2011 using the current edition of the guidelines. RESULTS: The mean postoperative follow-up period was 25.3 months. Radical nephrectomy was performed in 264 cases, whereas partial nephrectomy was performed in 193 cases. Including the 33 cases discovered after operation, the overall number of metastatic cases was 68 (14.9%). Using the current edition of the guidelines, the items of histologic grade, morphology of tumor invasion, tumor pseudocapsule, and intrarenal metastasis were all correlated with distant metastasis. CONCLUSION: This is the first report showing that each item on the current Japanese guidelines for renal cell cancer was useful for predicting metastasis.

Effects of dutasteride on lower urinary tract symptoms: a prospective analysis based on changes in testosterone/dihydrotestosterone levels and total prostatic volume reduction.

This study analyzed the effects of dutasteride on lower urinary tract symptoms based on the association between changes in the total testosterone (TT)/dihydrotestosterone (DHT) levels and total prostate volume (TPV) reduction. Sixty participants diagnosed with benign prostatic hyperplasia were given 0.5 mg of dutasteride daily for 52 weeks. Measures of TT and DHT levels, TPV and uroflowmetry were obtained before and after dutasteride treatment. Forty-three patients demonstrated a TPV reduction of ≥5% (Group 1), whereas the remaining 17 patients demonstrated a TPV reduction of <5% (Group 2). DHT suppression and DHT/TT ratio at baseline were significantly higher in Group 1 than Group 2. International Prostate Symptom Scores (IPSS) and uroflowmetry were significantly improved in both groups. In Group 2, nine patients demonstrated some improvement in IPSS (Group 2A), whereas eight did not (Group 2B). The rate of TT increase and improvement in voiding symptoms were significantly higher in Group 2A than Group 2B. Dutasteride-induced TPV reduction is dependent on individual 5-α reductase inhibitor activity. Some patients demonstrating smaller dutasteride-induced TPV reduction may experience an improvement in voiding symptoms owing to an increased level of testosterone.

Efficacy of two-time prophylactic intravenous administration of tazobactam/piperacillin for transrectal ultrasound-guided needle biopsy of the prostate.

BACKGROUND: Prevalence of fluoroquinolone (FQ)-resistant Escherichia coli has been recently increasing worldwide. We analyzed the incidence and characteristics of acute bacterial prostatitis after transrectal ultrasound-guided needle prostate biopsy (TRUSP-Bx) with prophylactic tazobactam/piperacillin (TAZ/PIPC) treatment as an alternative regimen. METHODS: A total of 391 patients who underwent TRUSP-Bx were included in the study. All patients received intravenous TAZ/PIPC (4.5 g) 30 minutes before and 6 hours after TRUSP-Bx. RESULTS: Acute bacterial prostatitis developed in six patients (1.5%); the frequency of its occurrence was significantly higher in patients in whom rectal disinfection was not performed (P < 0.05). These six patients developed clinical symptoms of acute bacterial prostatitis a median of 24 hours after the biopsy. Escherichia coli was isolated in urine or blood bacterial cultures in four cases, and Klebsiella pneumoniae in two cases. All of the isolated organisms showed excellent sensitivity to TAZ/PIPC. CONCLUSIONS: The incidence rate of acute prostatitis with prophylactic TAZ/PIPC was consistent with those reported previously with FQ-based regimens, despite the favorable sensitivity of isolated organisms. Two-time regimen of TAZ/PIPC may not always prevent the post-TRUSP-Bx infection, possibly due to the pharmacokinetic characteristics of TAZ/PIPC. However, if each case was considered individually to select the best setting and frequency of dosage of TAZ/PIPC, this can be an optimal prophylaxis in the era of widespread FQ-resistant microorganisms.

Simple Risk Stratification to Detect Prostate Cancer with High Gleason Score in Repeat Biopsies in a Population Screening Follow-up Study.

BACKGROUND: To investigate the clinical usefulness of percentage free prostate-specific antigen (%fPSA) and PSA velocity (PSAV) for detecting prostate cancer in repeat biopsies in a population-based screening cohort. PATIENTS AND METHODS: In total, 178 men with serum PSA levels within 2.1-10 ng/ml who underwent repeat biopsies after initial negative biopsy results, were enrolled. Prostate cancer detection rates with a Gleason score of 7 or more according to age, serum PSA, %fPSA, and PSAV were investigated. The cumulative probability of detecting cancer according to risk factors was also investigated. RESULTS: Out of 178 men who underwent repeat biopsy, 48 (27.0%) were diagnosed with prostate cancer during the observation period, and pathological examination revealed prostate cancer with a Gleason score of 7 or more in 17 patients (35.4%). In the multivariate logistic regression analysis, %fPSA ≤ 12 at repeat biopsy and PSAV >0.40 ng/ml/year were determined to be independent risk factors for prostate cancer, and %fPSA ≤ 12 at initial biopsy and PSAV >0.40 for cancer of Gleason score 7 or greater. The cumulative probabilities of developing high-grade cancer after 5 years were 55.8% and 4.0% in men with %fPSA ≤ 12 at initial biopsy and PSAV >0.40, and in men without both, respectively. There was a statistically significant difference in probabilities between groups by the log-rank test. CONCLUSION: The present results demonstrated that %fPSA and PSAV were predictors of prostate cancer with a Gleason score of 7 or more in repeat biopsy after a negative initial biopsy on a population follow-up basis.

Effects of testosterone replacement therapy on nocturia and quality of life in men with hypogonadism: a subanalysis of a previous prospective randomized controlled study in Japan.

OBJECTIVE: We investigated the effects of testosterone replacement therapy (TRT) on nocturia and general health among men with hypogonadism and nocturia. METHODS: From our previous EARTH study population, 64 patients with a clinical diagnosis of nocturia (two or more times per one night) and hypogonadism, comprising the TRT group (n = 31) and controls (n = 33), were included in this analysis. The TRT group was administered 250 mg of testosterone enanthate as an intramuscular injection every 4 weeks for 6 months. All patients responded to the following questionnaires: International Prostatic Symptoms Score (IPSS), Aging Male Symptoms (AMS) score and Short Form-36 health survey at baseline and 6-month visit. These categories were compared based on changes from baseline to the 6-month visit between TRT and control groups. RESULTS: At the 6-month visit, the TRT group had a significant decrease in IPSS question no. 7 and AMS question no. 4, whereas no significant changes were observed in the control group. Additionally, role limitation because of health program, vitality and mental health domains were significantly improved in the TRT group. CONCLUSIONS: Six-month TRT may improve nocturia, sleep conditions and quality of life among men with hypogonadism and nocturia.

[Treatment with recombinant thrombomodulin on disseminated intravascular coagulation caused by urinary tract infections; a retrospective comparative study with control cases].

We examined the efficacy of recombinant thrombomodulin (rTM) for treatment of patients with disseminated intravascular coagulation (DIC) caused by urinary tract infections. Thirteen DIC patients treated with rTM (rTM group) and 11 not receiving rTM (non-rTM group) were enrolled in this study. Blood data including coagulation markers collected before and after the treatment,a hospitalized term,and period of antibiotic treatment were compared. There were no significant differences in baseline characteristics between the two groups. Both groups showed significant improvement in all parameters such as blood biochemical data,coagulation markers,and DIC score 5-7 days after treatment. However, changes in platelet and DIC score from baseline to early phase (day 1-3) were significantly greater in the rTM group than in the non-rTM group (p＜0.05). In addition,changes in FDP value showed slight but not significant improvement in rTM group compared to the non-rTM group in the early treatment phase (p＝ 0.084). The period of antibiotic usage was significantly shorter in the rTM group,whereas the hospitalized term showed no significant difference between the groups. Definite adverse effects were not present in the rTM group. In conclusion,administration of rTM may have a beneficial effect in patients with DIC induced by urinary tract infections,compared with conventional treatment.

Age-specific reference range of prostate-specific antigen and prostate cancer detection in population-based screening cohort in Japan: verification of Japanese Urological Association Guideline for prostate cancer.

OBJECTIVES: To investigate the age-specific reference range of prostate-specific antigen and clinical characteristics of screening-detected cancer in prostate-specific antigen-based screening, and to verify the age-specific prostate-specific antigen cut-offs in the Japanese Urological Association Guidelines. METHODS: Prostate-specific antigen distributions were estimated in a total of 69,028 screening tests according to the age of the participants in population screening from 2000 to 2013. The age-specific reference range of prostate-specific antigen for detection of cancer was investigated by analyzing the receiver operating characteristic curves. Furthermore, the clinicopathological features of screening-detected cancer with serum prostate-specific antigen levels below the age-specific prostate-specific antigen cut-off in the Japanese Urological Association Guidelines were also investigated. RESULTS: Of all 69,028 screens, 2053 prostate biopsies (2.97%) were carried out and 549 cases of cancer (0.79%) were diagnosed. The 95th percentiles in all participants aged 54-59, 60-64, 65-69 and 70-75 years old were 2.90, 3.60, 4.10, and 4.70 ng/mL, respectively. The optimal prostate-specific antigen cut-offs for cancer detection determined from the receiver operating characteristic curves were 2.3 and 2.6 for the age ranges 54-69 and 70-75 years, respectively. These values were lower than the age-specific cut-offs in the Japanese Urological Association Guidelines. Of all 137 patients with prostate-specific antigen levels below the age-specific cut-offs in the Japanese Urological Association Guidelines, 80 (58.4%) had unfavorable clinicopathological features as active surveillance criteria. CONCLUSIONS: The age-specific reference range of prostate-specific antigen might be lower than that recommended in the Japanese Urological Association Guidelines. An individualized and natural history-adjusted screening system should be established for screening participants with low prostate-specific antigen level.

Cytological evaluation using liquid-based cytology in the male urogenital tract infected with human papillomavirus.

This study was performed to determine the associations between human papillomavirus (HPV) infection and cytological changes in the male glans and urethral samples. Two rubbed samples of the glans and distal urethra were collected from 160 patients with urethritis, and the collected cells were placed into preservative solution for liquid-based cytology. DNA was extracted from all samples, and ß-globin gene amplification, HPV-DNA test, and HPV genotyping were performed. After papanicolaou staining of each sample, cytological findings were assessed based on nine non-classic signs, and compared with the results of HPV-DNA test. Among the ß-globin positive samples, HPV (any type) was detected in 33 and 25% of the glans and urethra samples, respectively. High-risk HPV-DNA was detected in 25 and 15% of the glans and urethra samples, respectively. In the glans samples, cytological signs of HPV infection were observed in 17% of low-risk HPV-positive samples and in 58% of high-risk HPV-positive samples. Cytological atypia suspected to indicate penile intraepithelial neoplasia were observed in 17 and 33%, respectively. On the other hand, abnormal cells were observed in 29% of low-risk HPV-positive and 83% of high-risk HPV-positive urethral samples. Cytological atypia suspected to be urethral intraepithelial neoplasia was observed in 29 and 65%, respectively. In situ hybridization demonstrated the presence of HPV-DNA in the morphologically abnormal cells in 31 and 35% of high-risk HPV-positive glans and urethral samples, respectively. Cytological changes similar to cervical intraepithelial neoplasia in females could be detected in the HPV-positive glans and urethral samples.

Clinical characteristics and prostate-specific antigen kinetics of prostate cancer detected in repeat annual population screening in Japan.

OBJECTIVES: To clarify the present status regarding repeat examination in the annual population screening system in Japan, and to analyze the clinical characteristics and prostate-specific antigen kinetics of prostate cancer detected in this setting. METHODS: We summarized the annual individual data of prostate-specific antigen-based population screening in Kanazawa, Japan, and analyzed the prostate cancer detection rates at first and repeat screening. The clinical characteristics were compared between patients detected at first and repeat screening. The patients were classified according to favorable or unfavorable clinical characteristics of cancer, and prostate-specific antigen kinetics were compared between the two groups. RESULTS: From 2000 to 2011, 19 620 men participated in this screening program, and a total of 59 019 screenings were carried out. The total annual numbers of examinees increased, and the annual rates of first examinees gradually decreased. The annual detection rates of cancer at total screening decreased in the second year. The annual detection rate at first screening was not different from that in the first year. The rate of patients with favorable cancer features was significantly higher among patients detected at repeat screening than at first screening. The rates of patients with high prostate-specific antigen velocity and low prostate-specific antigen doubling time were significantly higher in unfavorable than favorable cancer patients in repeat screening. CONCLUSIONS: Repeat population screening could contribute to early detection of prostate cancer, and it seems that prostate-specific antigen kinetics might predict the cancer characteristics in repeat screening.

Effects of dutasteride on lower urinary tract symptoms and general health in men with benign prostatic hypertroplasia and hypogonadism: a prospective study.

INTRODUCTION: We investigated the effects of the relative increase in testosterone by dutasteride administration in patients with benign prostatic hyperplasia and hypogonadism on urinary symptoms or androgen-responsive general health. METHODS: Seventy-six patients were enrolled, and were taking 0.5 mg dutasteride daily for 52 weeks. Before and after treatment, all participants underwent blood test, and body mass index, prostate volume (PV), bone mineral density (BMD), post-voiding residual (PVR) volume, and muscle volume were measured. All patients responded to the questionnaires: International prostatic symptom score (IPSS), Overactive Bladder Symptom score (OABSS). Patients were divided into two groups according to the increase rate of total testosterone (TT): group A, ≥20% increase in TT level; group B, <20% increase or decrease. RESULTS: Baseline TT and free testosterone (FT) levels were significantly lower in group A than group B. Both groups showed marked improvement in PV and PVR. Group A showed significant improvement in IPSS and OABSS with a significant increase of FT level, whereas group B showed no significant change. Dutasteride treatment contributed to a significant increase in BMD in group A. CONCLUSIONS: Dutasteride treatment significantly improved urinary symptoms and BMD in patients with low baseline serum TT and FT levels.

Etiological correlation of human papillomavirus infection in the development of female bladder tumor.

The critical factors and etiological role of human papillomavirus (HPV) infection in the development of female bladder tumor were examined. Eighty-four female patients with primary bladder tumor were studied. After DNA extraction from each paraffin-embedded tissue, HPV-DNA and genotype were checked. In cases of all HPV-positive cases and some HPV-negative cases, in situ hybridization (ISH) for high-risk HPV-DNA, and immunohistochemical analysis for p16-INK4a were performed. HPV-DNA was detected in 5 (6.0%) of 84 eligible patients, and HPV16 was detected in 3 patients, and HPV6 and HPV52 was detected in one case, respectively. HPV-DNA was detected frequently in younger patients and in patients with a history of cervical cancer. In four high-risk HPV-positive cases, high-risk HPV-DNA was present in tumor tissues, and p16-INK4a was expressed moderately or strongly. Two cases had a past history of cervical cancer. In these 2 cases, the same HPV type (HPV16) was detected from bladder tumor and cervical cancer. High-risk HPV-DNA ISH signals and p16-INK4A expression were also detected widely in these cervical cancer tissues. HPV infection is likely to play an important role in the development of female bladder tumor at younger cases with a past history of cervical cancer.

Liquid-based urine cytology as a tool for detection of human papillomavirus, Mycoplasma spp., and Ureaplasma spp. in men.

Liquid-based urine cytology (LB-URC) was evaluated for cytological diagnosis and detection of human papillomavirus (HPV), Mycoplasma, and Ureaplasma. Midstream urine samples were collected from 141 male patients with urethritis and 154 controls without urethritis, and sediment cells were preserved in liquid-based cytology solution. Urethral swabs from urethritis patients were tested for the presence of Neisseria gonorrhoeae and Chlamydia trachomatis. Papanicolaou tests were performed for cytological evaluation. HPV, Mycoplasma, and Ureaplasma genomes were determined by PCR-based methods, and localization of HPV DNA in urothelial cells was examined by in situ hybridization (ISH). The ß-globin gene was positive in 97.9% of LB-URC samples from urethritis patients and in 97.4% of control samples, suggesting that high-quality cellular DNA was obtained from the LB-URC samples. HPV DNA was detected in 29 (21.0%) urethritis cases and in five (3.3%) controls (P < 0.05). HPV type 16 (HPV 16) was most commonly found in urethritis patients. Cytological evaluations could be performed for 92.1% of urethritis patients and 64.3% of controls. Morphological changes suggestive of HPV infection were seen in 20.7% of the HPV-positive samples, and ISH demonstrated the presence of HPV DNA in both squamous and urothelial cells in HPV-positive samples. Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma parvum, and Ureaplasma urealyticum were detected in 14.5%, 10.9%, 6.5%, and 12.3% of urethritis patients, respectively. The prevalence rates of these microorganisms (except Ureaplasma parvum) were significantly higher in urethritis cases than controls (P < 0.05). LB-URC is applicable for detection of HPV, Mycoplasma, and Ureaplasma. HPV infection occurs in urothelial cells, especially in gonococcal urethritis.

Etiologic role of human papillomavirus infection in bladder carcinoma.

BACKGROUND: The authors elucidated an etiologic role of human papillomavirus (HPV) infection in carcinoma of the bladder. METHODS: One hundred seventeen of 224 patients with bladder carcinoma who were treated between 1997 and 2009 were enrolled in this study. The presence of HPV DNA was tested on frozen carcinoma tissues that were obtained by transurethral resection using a polymerases chain reaction-based method. Localization of HPV was observed on archival tissue specimens by in situ hybridization (ISH) for high-risk HPV DNA. Cyclin-dependent kinase (CDK) inhibitor 2A (inhibits CDK4) (p16-INK4a) and minichromosome maintenance protein-7 (mcm-7)-surrogate markers for high-risk HPV-E7 oncoprotein-and HPV-L1 (capsid) protein expression were evaluated by immunohistochemistry. RESULTS: HPV types 16, 18, 31, 33, 52, and 58, and an unknown HPV type were detected in 18 of 117 samples (15%) from patients with bladder carcinoma. HPV16 was identified in 6 samples, HPV18 was identified in 4 samples, and HPV33 was identified in 3 samples. All were single HPV type infections. HPV was detected in 38% (12 of 28) of histologic grade 1 bladder carcinomas, 8.5% (6 of 71) of grade 2 bladder carcinomas, and in 0% (0 of 18) of grade 3 bladder carcinomas. Multivariate analysis indicated that younger age (<60 years; odds ratio [OR], 10.9; 95% confidence interval [CI], 2.6-45.3) and grade 1 tumors (OR, 4.5; 95% CI, 1.2-17.0) were associated with HPV infection. ISH analysis indicated that high-risk HPV DNA was localized in the nuclei of tumor cells of all HPV-positive samples. p16-INK4a and mcm-7 were expressed in 94% and 89% of HPV-positive carcinoma cells, respectively. HPV-L1 protein expression, which suggested reproductive HPV infection, was not observed in any carcinoma. CONCLUSIONS: The current results indicated that high-risk HPV is likely to be a causative agent of some low-grade bladder carcinomas that develop in younger patients.

Etiological role of human papillomavirus infection for inverted papilloma of the bladder.

The status of human papillomavirus (HPV) infection in urothelial inverted papilloma was examined in the present study. Formalin-fixed and paraffin-embedded tissues from eight cases of inverted papilloma of the bladder were studied. The presence of HPV-DNA was examined by modified GP5/6+PCR using archival tissue sections by microdissection. HPV genotype was determined with a Hybri-Max HPV genotyping kit. Immunohistochemical analysis for p16-INK4a, mcm7, HPV-E4, and L1, and in situ hybridization for the HPV genome were performed. HPV was detected in seven of eight cases (87.5%) of inverted papilloma. Three cases were diagnosed as inverted papilloma with atypia, while the remaining five were typical cases. HPV-18 was detected in two cases, including one inverted papilloma with atypia, and HPV-16 was detected in four cases, including one inverted papilloma with atypia. Multiple HPV type infection was detected in one typical case and one atypical case. High-risk HPV was present in all HPV-positive cases. Cellular proteins, p16-INK4a and mcm7, which are surrogate markers for HPV-E7 expression, were detected in all HPV-positive cases, and their levels were higher in inverted papilloma with atypia than in typical cases. In contrast, HPV-E4 and L1, which are markers for HPV propagation, were observed in some parts of the typical inverted papilloma tissue. High-risk HPV infection may be one of the causes of urothelial inverted papilloma, and inverted papilloma with atypia may have malignant potential.