Molecular Characterization of Testicular Germ Cell Tumors Using Tissue Microdissection.

Testicular germ cell tumors are among the most common malignancies seen in children and young adults. Genomic studies have identified characteristic molecular profiles in testicular cancer, which are associated with histologic subtypes and may predict clinical behavior including treatment responses. Emerging molecular technologies analyzing tumor genomics, transcriptomics, and proteomics may now guide precision management of testicular tumors. Laser-assisted microdissection methods such as laser capture microdissection efficiently isolate selected tumor cells from routine pathology specimens, avoiding contamination from nontarget cell populations. Laser capture microdissection in combination with next generation sequencing makes precise high throughput genetic evaluation effective and efficient. The use of laser capture microdissection (LCM) for molecular testing may translate into great benefits for the clinical management of patients with testicular cancers. This review discusses application protocols for laser-assisted microdissection to investigate testicular germ cell tumors.

Fluorescence In Situ Hybridization (FISH) Detection of Chromosomal 12p Anomalies in Testicular Germ Cell Tumors.

Gains of genetic material or internal rearrangements of chromosome 12p, including 12p overrepresentation or isochromosome 12p [i(12p)], are observed in virtually all germ cell tumors (GCT), in all histologic subtypes, and from various body locations. The chromosomal region involved in these alterations contains the growth and survival promoting oncogene KRAS (12p12.1). Gains or rearrangements of 12p characterize GCT from in situ to chemoresistant stages. Fluorescence in situ hybridization (FISH) detection of chromosome 12p anomalies is a sensitive and specific test for the diagnosis of germ cell tumors. Here we provide a detailed protocol for FISH detection of isochromosome 12p and chromosome 12p overrepresentation. The method is helpful for diagnosis of germ cell origin, and for selection of patients who may benefit from cisplatin-based chemotherapy.

Safety and feasibility of carotid revascularization in patients with cerebral embolic strokes associated with carotid webs and histopathology revisited.

INTRODUCTION: Carotid web is increasingly recognized as the cause of ischemic embolic strokes in younger patients. The best way to treat carotid web is debatable and carotid artery stenting (CAS) has been reported as a treatment for the carotid web in only a few case series. In this study we evaluate the safety and feasibility of CAS in symptomatic carotid webs and examined the histopathology of a carotid web. MATERIALS AND METHODS: At our institution between 2017 and 2019, 10 consecutive patients with symptomatic carotid webs were treated. We retrospectively analyzed the data for patient demographics, clinical presentation, imaging, treatment methodology and follow up. RESULTS: All the patients had presented with ipsilateral embolic stroke. The mean age at presentation was 50 years (range 37-71) with seven female and three male patients. All patients underwent CAS except one patient who underwent carotid endarterectomy (CEA). In one stented patient, there was significant hypotension in the post-procedural period lasting a week. The patients were followed for a mean of 5.5 months (range one day-12 months). No recurrent stroke or transient ischemic attack (TIA) occurred. Surgical pathological studies confirmed fibromuscular dysplasia in one specimen. CONCLUSION: In our experience CAS for carotid web is feasible and safe in patients presenting with ischemic embolic strokes.

Molecular evidence supporting the precursor nature of atypical adenomatous hyperplasia of the prostate.

Atypical adenomatous hyperplasia (AAH) of the prostate is characterized by lobular proliferation of closely packed small acini. It is hypothesized that AAH is a precursor lesion for low-grade prostate cancer arising from the transition zone. Telomere dysfunction is common during malignant transformation of epithelia. In this study, we investigate telomere shortening in AAH (n = 93), high-grade prostatic intraepithelial neoplasia (HGPIN) ( n = 68), and prostatic adenocarcinoma (PCA) ( n = 70) using quantitative fluorescence in situ hybridization. Twenty percent (19 of 93) of AAH specimens, 68% (46 of 68) of HGPIN, and 83% (58 of 70) of PCA showed significant telomere shortening. Thirty-two percent of AAH lesions had α-methylacyl-CoA racemase (AMACR) expression, a sensitive and specific marker for HGPIN and PCA. AMACR expression in AAH was seen more frequently in AAH foci with telomere shortening or coexisting PCA. Our findings indicate that a subset of AAH lesions have telomere shortening and AMACR expression, suggesting that these foci may be precursors for PCA.

Reshapable hydrogel tissue expander for ridge augmentation: Results of a series of successive insertions at the same intraoral site.

BACKGROUND: Oral mucosa expansion before ridge augmentation is a procedure to reduce soft tissue exposure and to improve bone graft density and volume after augmentation. This study explored a novel, shapeable hydrogel tissue expander (HTE) in intraoral sites that had undergone previous expansion and surgery. METHODS: Nine beagle dogs had all premolar teeth extracted and adjacent alveolar bone reduced. After at least 3 months healing hydrogels were placed at 4 sites in each dog: maxilla and mandible, right and left. After 6 weeks of expansion, the hydrogels were removed and measured for volume expansion and physical condition. Punch biopsies were taken of the expanded oral mucosa. After 3 months, a second hydrogel insertion was performed at each of the same sites. After this second expansion cycle, volume and hydrogel condition were recorded. Three dogs received ultrasound imaging of the hydrogels during the second expansion. Necropsy specimens were taken of both expanded and non-expanded oral mucosa. RESULTS: Within 2 weeks after HTE insertion in both first and second insertions, blood flow returned to the pre-insertion level. The first and second insertions resulted in linear oral mucosa gain of 8.13 mm, and 6.44 mm, respectively. First and second insertion hydrogels erupted from 4% of the first expansion sites, and 3% of the second expansion sites. There was no directional migration of the expanding hydrogel at any site. Histology found little inflammatory reaction to any hydrogel implant. CONCLUSION: Oral mucosa can be consistently and successfully expanded before bone graft for ridge augmentation even at sites with a history of prior surgeries.

Baseline Biomechanical Properties of Epithelia prior to Tissue Expansion in Dogs.

BACKGROUND: Soft-tissue deficiencies pose a challenge in a variety of disease processes when the end result is exposure of underlying tissue. Although multiple surgical techniques exist, the transposition of tissue from one location to another can cause donor-site morbidity, long incisions prone to dehiscence, and poor patient outcomes as a result. Use of tissue expansion prior to grafting procedures has been shown to have success in increasing available soft tissue to aid in repairing wounds. However, the current tissue expanders have biomechanical limits to the extent and rate of expansion that usually exceeds the tissue capacity, leading to incisional dehiscence or expander extrusion. Understanding the baseline biomechanical properties of the tissue to be expanded would provide useful information regarding surgical protocol employed for a given anatomical location. Therefore, the aim of this study was to test and compare the baseline (preexpansion) biomechanical properties of different common expansion sites in dogs. METHODS: Four samples measuring approximately 20 × 15 × 1 mm were harvested from 8 dogs. The samples were collected from the hard palate, alveolar mucosa, scalp, and chest of the animal and analyzed for stress, strain, maximum tangential stiffness, maximum tangential modulus, and tensile strength using a Texture Technologies TA.XT texture analyzer with corresponding biomechanical measurement software. Samples were compared as to their baseline biomechanical properties prior to any soft-tissue expansion. Histological sections of the samples were analyzed using hematoxylin eosin in an attempt to correlate the histological description to the biomechanical properties seen during testing. Summary statistics (mean, standard deviation, standard error, range) are reported for stress, strain, maximum tangential stiffness, maximum tangential modulus, and tensile strength and for the histological parameters by intraoral site. Analysis of variance was used to compare the biomechanical and histological parameters among the 4 locations while accounting for multiple measurements from each dog. RESULTS: The scalp had significantly higher maximum stress (σmax) than chest, mucosa, and palate (P < 0.0001), with no differences among the other 3 locations (P > 0.63). Scalp site also had significantly higher maximum tangential modulus (ε) than chest, mucosa, and palate (P < 0.006), with no differences among the other 3 locations (P > 0.17). The locations did not have significantly different maximum tangential stiffness (k; P = 0.72). Histologically, 2 separate patterns of collagen disruption were evident. CONCLUSION: Although different results were obtained than theorized, this study showed that the scalp had the greatest resiliency to expand prior to tearing, and the highest tangential modulus, with all sites having statistically similar modulus of elasticity. Based on this study, the scalp could be expanded more aggressively compared with the other sites.

Giant Cell Polymyositis and Myocarditis in a Patient With Thymoma and Myasthenia Gravis: A Postviral Autoimmune Process?

Thymomas are associated with autoantibody formation. The most common are anti-acetylcholine receptor antibodies, which correspond to myasthenia gravis (MG). Other autoantibodies, such as antistriational antibodies, can occur, but their relation to clinical syndromes is frequently uncertain. The etiology of antistriational antibodies is also poorly understood. In this case, a 61-year-old man with a history of thymoma was admitted with respiratory failure. The patient was positive for anti-acetylcholine receptor antibodies and antistriational antibodies. He developed cardiogenic shock and died within 2 days despite aggressive therapy. Laboratory studies revealed elevated cardiac enzymes and marked IgG elevation against Coxsackie A virus serotypes 9 and 24. Subclinical IgG elevations against additional Coxsackie A and Coxsackie B virus serotypes were also noted. Autopsy revealed lymphohistiocytic infiltrates with multinucleated giant cells in the myocardium and skeletal muscles, including the diaphragm. Giant cell polymyositis and myocarditis is a rare, lethal complication in patients with thymoma and MG. The pathogenesis is uncertain. An autoimmune process, possibly elicited by antistriational antibodies, has been suggested. The coexistence of antistriational antibodies and Coxsackie viral serologies has not been reported. This case may suggest that giant cell polymyositis and myocarditis in patients with thymoma and MG is a postviral autoimmune process.

Prognostic value of programmed death ligand 1, p53, and Ki-67 in patients with advanced-stage colorectal cancer.

Current prognostic indicators are ineffective for identifying advanced-stage colorectal cancer (CRC) patients with high risk of recurrence after surgical resection. We investigated the prognostic value of p53, Ki-67, and programmed death ligand 1 (PD-L1) in 254 patients with stage II and III CRC. The expression of p53 was positive in 63% of cases. Up-regulation of p53 was associated with smaller tumor size (P=.001) and higher Ki-67 labeling index (LI) (P=.031). The tumor Ki-67 LI was high (≥20%) in 197 (78%) of the patients. High Ki-67 LI was associated with higher TNM stage (P=.031), positive p53 expression (P=.031), and negative PD-L1 expression (P=.003). The 5-year relapse-free survivals (RFS) were 53% and 89%, respectively, for the p53-positive and Ki-67 LI-high patients and the p53-negative and Ki-67 LI-low patients (P<.001). In univariate analysis, negative p53 (P=.001), low Ki-67 LI (P=.006), low PD-L1 expression (P=.044), low TNM stage (P<.001), rectosigmoid location (P=.026), and small size (P=.013) were significantly related to RFS. In multivariate Cox regression analysis, positive p53 expression (hazard ratio [HR]: 2.48; 95% confidence interval: 1.34-4.59, P=.004), high Ki-67 LI (HR, 2.62; 95% CI, 1.12-6.14, P=.027) and high TNM stage (HR, 2.598; 95% CI, 1.55-4.37, P<.001,) were independent predictors of unfavorable prognosis. In summary, PD-L1, Ki-67, and p53 staining individually had significant prognostic value for patients with stage II and III CRC. Moreover, combining p53 H-score ≥35 and Ki-67 LI ≥20% identifies patients with poor clinical outcome.

Small-cell Carcinomas of the Urinary Bladder and Prostate: TERT Promoter Mutation Status Differentiates Sites of Malignancy and Provides Evidence of Common Clonality Between Small-cell Carcinoma of the Urinary Bladder and Urothelial Carcinoma.

BACKGROUND: Small-cell carcinoma (SCC) of the urinary bladder frequently appears alongside urothelial carcinoma, suggesting common clonality. TERT promoter mutations have been recently implicated in urothelial carcinogenesis. OBJECTIVE: To investigate the degree to which TERT promoter mutations are involved in SCC of the urinary bladder, the linked tumorigenesis between urothelial carcinoma and SCC of the urinary bladder, and the molecular distinctions between SCC of the urinary bladder and of the prostate. DESIGN, SETTING, AND PARTICIPANTS: We investigated TERT promoter mutations in 53 cases of SCC of the urinary bladder and in 26 cases of SCC of the prostate using laboratory-based studies of tissue samples and clinical data. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured the frequency of TERT promoter mutations in SCCs of the urinary bladder and prostate, and concordance of the mutation status between concurrent urinary bladder SCC and urothelial carcinoma. RESULTS AND LIMITATIONS: TERT promoter mutations were detected in 29/53 (55%) cases of urinary bladder and 0/26 (0%) cases of prostate SCC. Of 25 cases with concurrent urinary bladder SCC and non-small-cell components, all cases harbored identical TERT promoter mutation status in both phenotypes. CONCLUSIONS: TERT promoter mutations are found in more than half of urinary bladder SCCs. Mutation status is also identical in urothelial carcinoma and SCC components of concomitant malignancies, providing evidence of a common clonality. TERT promoter mutation status can differentiate SCC of the urinary bladder from prostate SCC, suggesting potential diagnostic use. PATIENT SUMMARY: Small-cell carcinoma of the urinary bladder shares a common clonal origin with conventional urothelial carcinoma and may arise from a heterogeneous subclone. TERT promoter mutations may have utility as a differential biomarker for determining the primary site of a genitourinary small-cell carcinoma.

Mucosal Perfusion Preservation by a Novel Shapeable Tissue Expander for Oral Reconstruction.

BACKGROUND: There are few methods for expanding oral mucosa, and these often cause complications such as tissue necrosis and expander eruption. This study examines mucosal blood perfusion following insertion of a novel shapeable hydrogel tissue expander (HTE). The canine model used subgingival insertion of HTE following tooth extraction and alveolar bone reduction. The primary goal of this study was to gain understanding of epithelial perfusion and reparative responses of gingival mucosa during HTE expansion. METHODS: Nine Beagle dogs underwent bilateral premolar maxillary and mandibular tooth extraction. Three to four months later, HTE-contoured inserts were implanted submucosally under the buccal surface of the alveolar ridge. After removal and following a 6- to 7-month period of healing, new HTE implants were inserted at the same sites. The area was assessed weekly for tissue perfusion and volume of expansion. Biopsies for histological analysis were performed at the time of expander removal. RESULTS: Within 2 weeks following the second insertion, blood flow returned to baseline (defined as the values of perfusion measurements at the presurgery assessment) and remained normal until hydrogel full expansion and removal. Volume expansion analysis revealed that the hydrogel doubled in volume. Histological assessment showed no macrophage or inflammatory infiltration of the mucosa. No superficial fibrosis, decreased vascularity, or mucosal change was seen. CONCLUSION: Maintenance of adequate tissue perfusion is a clinically important aspect of tissue expander performance to reduce risk of device loss or injury to the patient, particularly for areas with a history of previous surgeries.

Fluorescence in situ hybridization in surgical pathology: principles and applications.

Identification of recurrent tumour-specific chromosomal translocations and novel fusion oncogenes has important diagnostic, therapeutic and prognostic implications. Over the past decade, fluorescence in situ hybridization (FISH) analysis of tumour samples has been one of the most rapidly growing areas in genomic medicine and surgical pathology practice. Unlike traditional cytogenetics, FISH affords a rapid analysis of formalin-fixed, paraffin-embedded cells within a routine pathology practice workflow. As more diagnostic and treatment decisions are based on results of FISH, demand for the technology will become more widespread. Common FISH-detected alterations are chromosome deletions, gains, translocations, amplifications and polysomy. These chromosome alterations may have diagnostic and therapeutic implications for many tumour types. Integrating genomic testing into cancer treatment decisions poses many technical challenges, but rapid progress is being made to overcome these challenges in precision medicine. FISH assessment of chromosomal changes relevant to differential diagnosis and cancer treatment decisions has become an important tool for the surgical pathologist. The aim of this review is to provide a theoretical and practical survey of FISH detected translocations with a focus on strategies for clinical application in surgical pathology practice.

TERT promoter mutation status in sarcomatoid urothelial carcinomas of the upper urinary tract.

AIM: To determine TERT promoter mutation status as well as the expression of PAX8, GATA3, p63, p40, p53 and uroplakin III in 17 patients with the upper urinary tract sarcomatoid urothelial carcinoma. METHODS & RESULTS:  TERT C228T mutations were found in six of 17 cases (35%). p53 was expressed in 77% of these tumors. PAX8, GATA3, p40 and uroplakin III are less frequently expressed. Lymph node metastases were present in ten cases (59%). Eight patients (47%), including all three patients with TERT mutation, died of cancer within 2 years after surgery. CONCLUSION: Sarcomatoid carcinoma of the upper urinary tract is an aggressive tumor and the presence of TERT mutation may portend poor prognosis.

Clinical benefit of a precision medicine based approach for guiding treatment of refractory cancers.

PATIENTS AND METHODS: Patients with metastatic solid tumors who had progressed on at least one line of standard of care therapy were referred to the Indiana University Health Precision Genomics Program. Tumor samples were submitted for DNA & RNA next-generation sequencing, fluorescence in situ hybridization, and immunohistochemistry for actionable targets. A multi-disciplinary tumor board reviewed all results. For each patient, the ratio of progression-free survival (PFS) of the genomically guided line of therapy divided by the PFS of their prior line was calculated. Patients whose PFS ratio was ≥ 1.3 were deemed to have a meaningful improvement in PFS. RESULTS: From April 2014-October 2015, 168 patients were evaluated and 101 patients achieved adequate clinical follow-up for analysis. 19 of 44 (43.2%) patients treated with genomically guided therapy attained a PFS ratio ≥ 1.3 vs. 3 of 57 (5.3%) treated with non-genomically guided therapy (p < 0.0001). Similarly, overall PFS ratios (irrespective of cutoff) were higher for patients with genomically guided therapy vs non-genomically guided therapy (p = 0.05). Further, patients treated with genomically guided therapy had a superior median PFS compared to those treated with non-genomically guided therapy (86 days vs. 49 days, p = 0.005, H.R. = 0.55, 95% C.I.:0.37-0.84). CONCLUSION: Patients with refractory metastatic cancer who receive genomically guided therapy have improved PFS ratios and longer median PFS compared to patients who do not receive genomically guided therapy.

Telomerase reverse transcriptase (TERT) promoter mutation analysis of benign, malignant and reactive urothelial lesions reveals a subpopulation of inverted papilloma with immortalizing genetic change.

AIMS: To understand more clearly the genetic ontogeny of inverted papilloma of urinary bladder, we analysed telomerase reverse transcriptase (TERT) promoter mutation status in a group of 26 inverted papillomas in comparison with the mutation status of urothelial carcinoma with inverted growth (26 cases), conventional urothelial carcinoma (36 Ta non-invasive urothelial carcinoma, 35 T2 invasive urothelial carcinoma) and cystitis glandularis (25 cases). METHODS AND RESULTS: TERT promoter mutations in inverted papilloma, urothelial carcinoma with inverted growth, urothelial carcinoma and cystitis glandularis were found in 15% (four of 26), 58% (15 of 26), 63% (45 of 71) and 0% (none of 25), respectively. C228T mutations were the predominant mutations (97%) found in bladder tumours, while C250T aberrations occurred in approximately 3% of bladder tumours. In the inverted papilloma group, TERT mutation occurred predominantly in female patients (P = 0.006). Among urothelial carcinomas, TERT promoter mutation status did not correlate with gender, histological grade or pathological stage. CONCLUSIONS: TERT promoter mutations were found in 15% of inverted papillomas. Our data suggest that there is a subpopulation of inverted papilloma that shares a carcinogenetic pathway with urothelial carcinoma with inverted growth and conventional urothelial carcinomas. Caution is warranted in exploring TERT promoter mutation status as a screening or adjunct diagnostic test for bladder cancer.

Incidental prostate cancer in Asian men: high prevalence of incidental prostatic adenocarcinoma in Chinese patients undergoing radical cystoprostatectomy for treatment of bladder cancer and selection of candidates for prostate-sparing cystectomy.

BACKGROUND: Previous studies report a low prevalence of incidental prostate cancer in Chinese patients (3-7%). We evaluated incidental prostatic adenocarcinoma (PCa) and urothelial carcinoma (UCa) involvement of the prostate in cystoprostatectomy specimens. METHODS: We analyzed 340 cystoprostatectomy specimens from patients who underwent radical cystoprostatectomy for the treatment of bladder cancer in China from 2004 to 2014. None of the patients had known prostate cancer prior to cystoprostatectomy. RESULTS: Overall, 180 (53%) patients had either PCa or UCa in the prostate. We found that 95 (28%) had PCa and 115 (34%) had UCa involvement of prostate. The rate of incidental prostate cancer was 21% and 31%, respectively, from two study periods (2004-2008 and 2009-2014). Among the 95 patients with PCa, 19 (20%) had Gleason score of ≥7, nine (10%) had PCa tumor volume >0.5 cc, and eight (8.4%) had extracapsular extension. Of the 115 with prostatic UCa, 61 had prostatic urethra and/or periurethral prostatic duct involvement only, while 54 had prostatic stromal invasion. Age (odds ratio [OR] = 1.04, P = 0.001), increasing stage of bladder tumor (OR = 1.28, P = 0.005), multifocal tumors of bladder (OR = 3.22, P < 0.001), carcinoma in situ (CIS) in the bladder (OR = 5.52, P < 0.001), and bladder neck involvement (OR = 6.12, P < 0.001) were strongly associated with prostatic UCa. CONCLUSIONS: The rate of incidental PCa in cystoprostatectomy specimens in China has increased over the last decade. Patients with advanced age, elevated serum PSA level, advanced bladder tumor stage, multifocal bladder tumors, CIS in the bladder, and tumor location at the bladder neck should be excluded as candidates for prostate-sparing cystectomy.

Small cell carcinoma of the prostate: molecular basis and clinical implications.

Small cell carcinoma of the prostate (PSCC) is a rare and highly aggressive malignancy with a dismal prognosis. Most patients present with advanced disease, including metastases to bone, viscera, and the central nervous system. Histologically, PSCC is indistinguishable from its pulmonary counterpart. Although PSCC may occur in pure form, as in small cell lung carcinoma, it also occurs in conjunction with conventional glandular prostate carcinoma, and may evolve from conventional adenocarcinoma during the course of hormonal therapy. Immunohistochemical staining is extremely helpful in establishing the diagnosis, a prerequisite, as in small cell lung cancer, for optimal therapeutic strategy. Currently, combinations of surgical resection, chemotherapy, and radiation therapy represent the main treatment options. Improvement in survival may depend upon the identification of new molecular markers to facilitate earlier diagnosis and the development of novel targeted therapies. This review will discuss general aspects of PSCC, focusing on ways in which our understanding of PSCC has been advanced by studies of the histopathologic, immunohistochemical and molecular alterations in this disease.

Arteriovenous Malformation Masquerading as a Bladder Tumor. A Case Report.

BACKGROUND: Arteriovenous malformation (AVM) of the urinary bladder is an extremely rare benign vascular lesion. The clinical significance of bladder AVM lies in its presentation with painless hematuria and a hyperemic sessile bladder wall mass. CASE REPORT: A 47-year-old man presented with irritative symptoms and hematuria. Cystoscopically the lesion appeared as an erythematous, broad-based mass obscuring the right ureteral orifice. The patient underwent cystoprostatectomy for suspected mass lesion. Histologically the bladder tumor was composed of numerous malformed blood vessels of various calibers with myxoid degeneration. Immunohistochemically the bland endothelial cells lining in the vessels were reactive for markers of CD31 and CD34. Ki67 index was < 1%. The patient was free of disease 24 months after surgery. CONCLUSION: Our findings broaden the morphologic spectrum of bladder arteriovenous malformation and emphasize its deceptive presentation.

The expression patterns of p53 and p16 and an analysis of a possible role of HPV in primary adenocarcinoma of the urinary bladder.

BACKGROUND: Primary adenocarcinoma of the urinary bladder is rare. The molecular and cellular events leading to its pathogenesis are not well delineated. The goal of this study was to investigate p53 and p16 expression, as well as HPV status, in a relatively large series of primary bladder adenocarcinomas. MATERIALS AND METHODS: Thirty six cases of urinary bladder adenocarcinoma were chosen from participating institutions. The diagnosis and available clinical history were reviewed in each case. Immunostains for p53, p16 and HPV and high-risk and low-risk HPV-ISH were performed on all tumors. RESULTS: Patients had an average age of 61 years with a male predominance (1.5 ∶ 1 male ∶ female ratio). The average tumor size in cystectomy specimens was 4.3 cm. Of the cases managed by transurethral resection, 40% were pT2 at the time of diagnosis. In cystectomy specimens, 77% were either pT3 or pT4. Strong nuclear p16 expression was seen in 67% of all cases and p53 expression was present in 58% of the cases. Expression of both markers was seen in 33% of cases. Expression of p16 or p53 alone was present in 12 (33%) and 9 (25%) cases, respectively. Neither marker was expressed in only 3 (8%) of the tumors. No significant correlation between clinical variables and any of the markers we studied was identified. No HPV infection was detected in any case. CONCLUSIONS: Expression of p53 and/or p16 is very common in urinary bladder adenocarcinoma. These findings implicate a high likelihood that alterations in these cell cycle proteins contribute to the pathogenesis of these tumors. Despite frequent immunohistochemical labeling for p16, no evidence of HPV infection was found.