Human papillomavirus (HPV)-induced neoplasia in the urinary bladder: a missing link?

The discovery that the role human papillomavirus (HPV) plays in the induction of human cancer represents an important achievement in oncologic research. It has taken on even greater importance since the development of vaccines, which promise the hope of preventing these cancers from ever occurring. Because of these important implications, many have attempted to determine a possible role for the virus in cancers of the urinary bladder-an organ in close anatomic proximity to the primary sites of HPV-induced neoplasia and one which already has an established oncogenic infectious agent in Schistosoma haematobium. Here we review the current literature exploring this possible role in the most common subtype of cancer of the urinary bladder, urothelial carcinoma, and two much more rare histologic subtypes that have well established roles for HPV-induced neoplasia in other anatomic sites-squamous cell carcinoma and adenocarcinoma.

Rapid progression of primary cutaneous gamma-delta T-cell lymphoma with an initial indolent clinical presentation.

Primary cutaneous gamma-delta T-cell lymphoma (CGD-TCL) is a rare cutaneous T-cell lymphoma characterized by a rapidly progressive clinical course and a poor prognosis. We report a case of a 52-year-old man with a 10-year history of erythematous nodules and a rapid terminal progression diagnosed as CGD-TCL. Biopsies taken at the time of progression showed a dense lymphocytic infiltrate involving the subcutaneous adipose tissue and deep dermis. One of the biopsies displayed much more limited involvement by CGD-TCL that was nearly identical to the biopsies of the erythematous lesions 10 years before. In conclusion, this case demonstrates a case of CGD-TCL presenting as a longstanding indolent disease with a rapid terminal progression. The indolent clinical course and histological heterogeneity make diagnosing this entity during the initial stage extremely challenging. This case underscores a diverse clinical presentations and a need to consider CGD-TCL in patients showing subcutaneous lesions with an indolent clinical course.

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.

Cytoplasmic OCT4 staining is a sensitive marker of neuroendocrine differentiation.

Previous studies by the authors have described a novel cytoplasmic staining pattern with OCT4 in normal adrenal medullary tissue and in paragangliomas. We aimed to determine if this type of staining is found in other neuroendocrine tissues by examining a broad range of neuroendocrine tumors. Fifty neuroendocrine tumors of various grades and primary organ sites were selected. All cases were immunostained with OCT4 and Ki-67. OCT4 reactivity was then scored for intensity (0-3+) and extent (0-3+). Ki-67 proliferation index was scored as a percentage of total tumor cells. Immunoelectron microscopy was performed to determine precise location of antibody binding within cells. Immunoreactivity was seen in 26 (96%) of 27 cases of carcinoid tumors. The same type of strong staining was seen in 4 (67%) of 6 moderately differentiated neuroendocrine tumors. Only 2 (12%) of 17 poorly differentiated neuroendocrine tumors showed similar staining. A strong, inverse correlation was seen with OCT4 and Ki-67 index. Immunoelectron microscopy showed binding of OCT4 antibody to neurosecretory granules. Cytoplasmic staining of OCT4 is a sensitive marker of neuroendocrine differentiation that has yet to be described in any other tissue or tumor type. These findings show that this antibody has a high affinity for well- to moderately differentiated neuroendocrine tumors. Although comparative studies with other markers and a more extensive analysis of other tissue types are necessary, cytoplasmic staining of OCT4 may prove to be a useful immunostain in the diagnosis of neuroendocrine tumors.

EGFR alterations and EML4-ALK rearrangement in primary adenocarcinoma of the urinary bladder.

The identification of mutations in epidermal growth factor receptor (EGFR) and translocations involving anaplastic lymphoma kinase (ALK) in lung adenocarcinoma has drastically changed understanding of the disease and led to the development of targeted therapies. Adenocarcinoma of the urinary bladder is rare and poorly understood at the molecular level. We undertook this study to determine whether EGFR mutations, increases in EGFR copy number, or ALK translocations are present in these tumors. Twenty-eight cases of primary bladder adenocarcinoma were analyzed. For EGFR mutational analysis, PCR-amplified products were analyzed on the Q24 Pyrosequencer with Qiagen EGFR Pyro Kits. All cases were analyzed via fluorescence in situ hybridization (FISH) using Vysis ALK Break Apart FISH Probes for detection of ALK chromosomal translocation and Vysis Dual Color Probes to assess for increased gene copy number of EGFR. None of the 28 cases examined showed mutational events in EGFR or ALK rearrangements. EGFR polysomy was seen in 10 out of 28 (36%) cases. No correlation with EGFR polysomy was seen in the tumors with respect to age, histologic subtypes, pathologic stage, or lymph node metastasis. In summary, EGFR mutations and ALK rearrangements do not appear to be involved in the development of primary adenocarcinoma of the urinary bladder. A subgroup of cases (36%), however, demonstrated increased gene copy number of EGFR by FISH.

Expression of NFkappaB, ICAM1, and VCAM1 in rheumatic heart disease with atrial fibrillation.

OBJECTIVE: To examine the expression of nuclear factor kappaB (NFkappaB), intercellular adhesion molecule 1 (ICAM1), and vascular cell adhesion molecule 1 (VCAM1) levels in rheumatic heart disease patients who suffer from atrial fibrillation and those who do not. STUDY DESIGN: Twenty-six patients with rheumatic heart disease were enrolled. Ten patients had no history of atrial fibrillation and 16 had atrial fibrillation. Atrial tissue was obtained from the right atrial appendage during heart surgery. The expression levels of NFkappaB, ICAM1, and VCAM1 were examined with immunohistochemical staining. RESULTS: Myocardial inflammation and fibrosis were both increased in patients with atrial fibrillation. The levels of NFkappaB, ICAM1, and VCAM1 were significantly elevated in patients with atrial fibrillation as compared with the control group (all p < 0.05). CONCLUSION: Overexpression of NFkappaB, ICAM1, and VCAM1 may be involved in the development and maintenance of atrial fibrillation in patients with rheumatic heart disease.

Human papillomavirus is not an etiologic agent of urothelial inverted papillomas.

Inverted papilloma of the urinary bladder is rare, accounting for <1% of all bladder neoplasms. Although there is general consensus that inverted papilloma is benign in nature, little is known about its pathogenesis. Some have suggested that human papillomavirus (HPV) plays an etiologic role in the development of this neoplasm. These claims have not been adequately substantiated, and there is controversy as to the role of HPV in other urinary bladder neoplasms as well. To further investigate a possible etiologic role of HPV in urothelial neoplasia, we evaluated 27 inverted papillomas of the urinary bladder for the presence of HPV. Both immunohistochemical and in situ hybridization (ISH) studies for HPV and immunohistochemical analysis for p16, a surrogate marker for HPV infection, were used to assess HPV infection status. In the urinary bladder inverted papillomas of these 27 patients (age range, 35 to 78 y; M:F ratio, 11:1), no HPV was detected by HPV immunohistochemistry or by ISH. Immunoreactivity to p16 was detected in 11/27 (41%) of the cases. Expression of p16 is seen inconsistently within these neoplasms and does not correlate with the presence of HPV antigens or genes by immunohistochemistry or ISH, respectively. Therefore, p16 is not a reliable surrogate marker for HPV infection in urothelial inverted papilloma. Our findings indicate the absence of HPV in urothelial inverted papillomas. HPV testing should not be used as a diagnostic adjunct for inverted papilloma cases.

Cytoplasmic staining of OCT4 is a highly sensitive marker of adrenal medullary-derived tissue.

OCT4 immunostaining has become an essential resource in diagnosing germ cell neoplasia. OCT4 is a transcription factor with a characteristic nuclear staining pattern specific to germ cell neoplasms. Our institution has observed that paraganglionic tissue consistently displayed intense cytoplasmic staining by utilizing monoclonal OCT4 antibody, and we intended to determine whether OCT4 could provide additional diagnostic utility in adrenal tumors. We used monoclonal and polyclonal OCT4 antibodies for comparison of staining patterns and intensities. Thirty-eight pheochromocytomas (8 metastatic), 22 adrenal cortical carcinomas (2 metastatic), 15 metastatic tumors to the adrenal glands, and 10 normal adrenal glands containing cortical and medullary tissue were immunostained with OCT4. A 4-tier system (0 to 3), for recording intensity and extent of cytoplasmic staining, was used. All 30 primary pheochromocytomas displayed strong and diffuse (3+3) cytoplasmic immunoexpression. Six of 8 metastatic pheochromocytomas showed strong immunoexpression (3+3), whereas the remaining 2 showed moderate intensity (2+3). All 22 adrenal cortical carcinomas, including metastatic cases, were completely negative. Only 2 metastatic tumors to the adrenal gland showed weak, cytoplasmic positivity: a small cell carcinoma and a Merkel cell carcinoma. Controls stained in an appropriate nuclear manner. Immunoelectron microscopy demonstrated the antibody interacting with neurosecretory granules. To our knowledge, the cytoplasmic expression of OCT4 in adrenal medulla and pheochromocytoma has not been specifically studied. The goal of this study is to analyze the immunoreactivity of adrenal cortical carcinoma and pheochromocytoma to OCT4 and determine the sensitivity and specificity of this particular staining pattern and to compare monoclonal and polyclonal antibodies.

The spectrum of histopathologic findings in vesical diverticulum: implications for pathogenesis and staging.

Diverticula are saccular evaginations of urinary bladder mucosa that are encountered in all age groups with a prevalence of 1% to 10%. Intradiverticular neoplasms pose diagnostic and management challenges. The aim of this study was to document the common morphologic changes and neoplasms found in a large series of adult and pediatric vesical diverticula. A total of 174 diverticula from 133 patients were reviewed including 48 pediatric (mean age, 7.1 years) and 85 adult (mean age, 63.93 years); 92% were male. Of the 85 nonneoplastic cases, prominent morphologic findings included significant chronic inflammation (59), granulomatous inflammation including foreign body giant cell reaction (6), acute inflammation (7), squamous metaplasia (9), cystitis glandularis (10), and nephrogenic metaplasia (2). The pediatric cases showed no malignancy. Thirty-three of the 48 neoplastic cases had high-grade urothelial carcinoma, 4 had carcinoma in situ, 7 had low-grade papillary urothelial carcinoma, 2 had primary squamous cell carcinoma, 1 had primary melanoma, and 1 had urothelial dysplasia. Nine of the neoplastic cases had variant morphology. Diverticula from 31 cases were involved by primary tumors, of which 6 had coexisting intravesical neoplasia (3 had carcinoma in situ with invasion elsewhere). In 19 of 33 high-grade urothelial carcinomas, infiltration into adjacent fat was noted. Seven of these cases arose within diverticula. Diverticula may harbor neoplasms, most commonly urothelial carcinoma. Attenuation of the muscle layer associated with diverticulum formation may facilitate tumor invasion into peridiverticular soft tissues. It is emphasized that pT2 stage should be eliminated to avoid the confusion in staging these neoplasms.

KRAS mutation is present in a small subset of primary urinary bladder adenocarcinomas.

AIMS: To determine whether KRAS mutations occur in primary bladder adenocarcinoma. METHODS AND RESULTS: Twenty-six cases of primary urinary bladder adenocarcinoma were analysed. DNA was extracted from formalin-fixed, paraffin-embedded tissue and amplified with shifted termination assay technology, which recognizes wild-type or mutant target sequences and selectively extends detection primers with labelled nucleotides. A mutation in KRAS was found in three (11.5%) of 26 primary bladder adenocarcinomas. Two of these three cases exhibited a G13D mutation, whereas the remaining case contained a mutation in G12V. None of the ten cases of urothelial carcinoma with glandular differentiation displayed KRAS mutation. Colonic adenocarcinoma contained a KRAS mutation in 18 (33%) of 55 cases. There was no distinct difference with regard to grade, stage or outcome according to the limited clinicopathological data available. However, the two youngest patients, aged 32 and 39 years, in our study group, with a mean population age of 61 years, were found to have mutations in KRAS. CONCLUSIONS: KRAS mutations are present in a small subset of primary urinary bladder adenocarcinomas. Future clinical trials for treatment of bladder adenocarcinoma, employing targeted therapies similar to those used for treatment of colon cancer, may also benefit from the predictive implications of KRAS mutational testing.

p16 expression is not associated with human papillomavirus in urinary bladder squamous cell carcinoma.

Squamous cell carcinoma of the urinary bladder is unusual and of unknown etiology. There is a well-established association between human papillomavirus (HPV) infection and the development of cervical and head/neck squamous cell carcinomas. However, the role of HPV in the pathogenesis of squamous cell carcinoma of the urinary bladder is uncertain. The purposes of this study were to investigate the possible role of HPV in the development of squamous cell carcinoma of the urinary bladder and to determine if p16 expression could serve as a surrogate marker for HPV in this malignancy. In all, 42 cases of squamous cell carcinoma of the urinary bladder and 27 cases of urothelial carcinoma with squamous differentiation were investigated. HPV infection was analyzed by both in situ hybridization at the DNA level and immunohistochemistry at the protein level. p16 protein expression was analyzed by immunohistochemistry. HPV DNA and protein were not detected in 42 cases of squamous cell carcinoma (0%, 0/42) or 27 cases of urothelial carcinoma with squamous differentiation (0%, 0/15). p16 expression was detected in 13 cases (31%, 13/42) of squamous cell carcinoma and 9 cases (33%, 9/27) of urothelial carcinoma with squamous differentiation. There was no correlation between p16 expression and the presence of HPV infection in squamous cell carcinoma of the bladder or urothelial carcinoma with squamous differentiation. Our data suggest that HPV does not play a role in the development of squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation. p16 expression should not be used as a surrogate marker for evidence of HVP infection in either squamous cell carcinoma of the urinary bladder or urothelial carcinoma with squamous differentiation as neither HVP DNA nor protein is detectable in these neoplasms.

Bladder diverticulum: clinicopathologic spectrum in pediatric patients.

Urinary bladder diverticula are a relatively rare finding in both the adult and pediatric population. Their presence in the adult population has long been associated with the development of urothelial carcinoma within the lesion. Our goal is to analyze a relatively large pediatric patient population with urinary bladder diverticula to expand the body of knowledge on the associated clinical symptomatology, congenital syndromes associated with the entity, and treatment methods and to further investigate if there is any reason to suspect malignant transformation within the pediatric population. A search for pediatric patients (0-19 years of age) from 1990 to 2011 revealed 47 patients with 60 diverticula within the specified age range. Clinical records and histologic slides for all cases were pulled for review, and statistical analysis was performed on the results. The most common findings were vesicoureteral reflux (68%), recurrent urinary tract infection (55%), and hydronephrosis (40%). Fourteen of 47 (30%) patients had an associated congenital syndrome/malformation. Diverticular size range was 0.5-10 cm with a mean of 2.56 cm. No patient was found to have overt malignancy or dysplastic changes within the diverticula or bladder at the time of pathologic evaluation. High association with recognizable clinical symptoms and additional urinary tract abnormalities leads to early identification and treatment. A sizable percentage of those found to have bladder diverticula within the pediatric population will have a congenital syndrome. No association with malignancy is seen within pediatric bladder diverticula; it is an extremely unlikely event in these young patients.

Molecular pathology of lung cancer: key to personalized medicine.

The majority of lung adenocarcinoma patients with epidermal growth factor receptor- (EGFR) mutated or EML4-ALK rearrangement-positive tumors are sensitive to tyrosine kinase inhibitors. Both primary and acquired resistance in a significant number of those patients to these therapies remains a major clinical problem. The specific molecular mechanisms associated with tyrosine kinase inhibitor resistance are not fully understood. Clinicopathological observations suggest that molecular alterations involving so-called 'driver mutations' could be used as markers that aid in the selection of patients most likely to benefit from targeted therapies. In this review, we summarize recent developments involving the specific molecular mechanisms and markers that have been associated with primary and acquired resistance to EGFR-targeted therapy in lung adenocarcinomas. Understanding these mechanisms may provide new treatment avenues and improve current treatment algorithms.

Lymphadenectomy in urologic oncology: pathologic considerations.

Lymphadenectomy (LAD) is an important staging and treatment modality of oncologic surgery. LAD in genitourinary malignancies presents inherent difficulties to the urologist and pathologist because of the differences in anatomic sites and primary histologic type. This review focuses on pathologic evaluation and how communication between urologist and pathologist is necessary to provide optimal care. Recommendations covering general specimen submission and processing are discussed, as well as more specific recommendations concerning the kidney, upper urinary tract, urinary bladder, prostate, testes, and penis. Emerging areas of prognostic significance and the impact that improved molecular techniques are contributing to diagnostic interpretation are highlighted.

EMI and the first CT scanner.

The invention and development of the CT scanner is one of the most fascinating tales in the history of radiology. It includes of one of the 20th century's most important recording companies, perhaps the most influential recording group of all time, and a Nobel laureate in medicine and physiology who never attended medical school or earned a PhD. The story of the CT scanner offers important lessons for radiologists on the interaction between medicine and business that are at least as important today as they were decades ago.