High-grade Urothelial Cell Carcinoma Research Articles

A case of large-cell undifferentiated carcinoma of the bladder

Abstract Large-cell undifferentiated carcinoma of the urinary bladder is an extremely rare and aggressive neoplasm. We present a unique case of painless gross hematuria and a past surgical history of cystolithotomy. The patient underwent transurethral resection of the bladder tumor, which revealed high-grade urothelial cell carcinoma with lamina propria involvement. Subsequent radical cystoprostatectomy with orthotopic neobladder urinary diversion and pelvic lymphadenectomy was performed, and the postoperative pathologic examination indicated large-cell undifferentiated. This case report highlights the importance of accurate diagnosis and management for this rare malignancy and adds to the limited existing literature on Large-cell undifferentiated carcinoma.

The First Ever Robotic-Assisted Laparoscopic Radical Nephrectomy with Inferior Vena Cava Thrombectomy Performed in Thailand: A Case Report of Atypical Presentation of Urothelial Carcinoma with Tumor Thrombus

Background: Robotic-assisted surgery was proposed as an alternative to open surgery for management of inferior vena cava (IVC) thrombus together with radical nephrectomy in complex renal mass. Here, the authors reported the first case of this type to be managed via this surgical technique in Thailand. Case Report: A 76-year-old Thai female presented with right renal mass with tumor thrombus in the IVC extending 3 cm above the level of the renal vein. The presumed diagnosis was renal cell carcinoma of the right kidney with level 2 tumor thrombus in IVC, clinical staging T3bN0M0. The patient underwent robotic-assisted laparoscopic IVC thrombectomy together with right radical nephrectomy at Siriraj Hospital (Bangkok, Thailand) in May 2020. Results: The operation proceeded uneventfully without immediate complication. The postoperative reduction of IVC diameter was approximately 30%. Total IVC clamp time was 50 minutes, operative time was five hours, with docking time of 20 minutes and console time of 250 minutes, estimated intraoperative blood loss was 2,600 mL, and length of hospital stay was four days. At 30-days and 90-days postoperation, no thromboembolic event or compromising lower extremity venous return was detected. The pathological report revealed high-grade urothelial cell carcinoma with invasion into perinephric fat. Carcinoma involvement was observed in the tumor thrombus and IVC wall (T4N0M0). Conclusion: Robotic-assisted surgery of the IVC is a complex operation that requires robotic surgical proficiency and a highly experienced team. The observed success in the present case demonstrated the feasibly of this procedure in Thailand. Additional benefits include less postoperative pain, reduced blood loss, smaller surgical wound size, and shorter length of hospital stay. Keywords: Robotic-assisted laparoscopic radical nephrectomy; Inferior vena cava thrombectomy; Thailand

Diagnostic and Cost Implications of the 2020 AUA Microhematuria Guidelines: Modeling Impact in a Large Public Health Care System.

We sought to model the diagnostic recommendations and associated costs of new hematuria guidelines regarding referral patterns, procedure utilization and urothelial cell carcinoma (UCC) detection. Patients with microhematuria were identified retrospectively. Initial encounter data were collected from January 2017 to May 2018 from a large public health care system; followup was continued to December 2020. Risk stratification was performed based on the American Urological Association 2020 microhematuria guidelines, and disease outcomes were analyzed within this framework. The guideline-recommended workups and costs were modeled; cost data were sourced from the Centers for Medicare & Medicaid Services Medicare Physician Fee Schedule and Clinical Laboratory Fee Schedule for 2020. Modeled diagnostic volumes and costs were assessed for 2020 and 2012 microhematuria guidelines, respectively. Of the 3,789 patients included for analysis, 1,382 (36.5%), 1,026 (27.1%) and 1,381 (36.4%) were retroactively stratified as low risk, intermediate risk (InR) and high risk (HiR), respectively. A total of 19 cases of UCC (17 bladder, 2 upper tract) were diagnosed, of which 84% were HiR. For high-grade UCC, 92% of cases were HiR. The 2020 guidelines recommended renal ultrasound for 1,117 InR cases, computerized tomography urogram (CTU) for 1,476 HiR cases, and cystoscopy for 2,593 InR and HiR cases combined. Total costs were $1,905,236 (2012) versus $1,260,677 (2020), driven mainly by CTU costs. Per-cancer detected costs were $100,276 (2012) versus $61,760 (2020). In retrospect, the 2020 guidelines would have effectively risk-stratified microhematuria cases for detection of malignancies. As compared to the 2012 guidelines, application of the 2020 guidelines would result in significant changes to diagnostic and procedural volumes, while substantially reducing total and per-patient costs.

The COVID-19 Catalyst: Analysis of a Tertiary Academic Institution's Rapid Assimilation of Telemedicine.

Introduction:The COVID-19 pandemic forced all urology practices to reconsider the necessity of face-to-face office encounters. Seeking to reduce patient exposure, our urologic oncology office made an immediate transition to telemedicine and this study reports our experience.Methods:Beginning March 17, 2020 the urologic oncology department committed to see all patients via telemedicine, unless they needed a cystoscopy for high grade urothelial cell carcinoma or recent gross hematuria, or required removal of a Foley catheter or surgical drain. March 17 was assigned day 1, and for the next 14 days rates of face-to-face, audio and audiovisual encounters were recorded. A telephone survey was conducted with all patients who participated in an audiovisual encounter.Results:In analyzing the numbers of face-to-face, audio and audiovisual encounters, after day 5 more patients participated in audiovisual encounters than any other modality. By day 10 no nonessential face-to-face encounter occurred. There was an 80.4% response rate to our survey. Average patient account setup time was 10.5 minutes and 35.1% required assistance from our office to set up their account, averaging 7.1 minutes. No-show rates of face-to-face encounters were significantly higher than for audiovisual encounters (face-to-face 67%, audiovisual 17%, p <0.001). Overall 82% of patients surveyed were likely to elect for a telemedicine encounter over a face-to-face encounter for a routine visit during future flu seasons.Conclusions:The current study describes the initial adoption, early clinical experience and patient impressions of rapid implementation of telemedicine during the COVID-19 pandemic.

Diagnostic Agreement for High-Grade Urothelial Cell Carcinoma in Atypical Urine Cytology: A Nationwide Survey Reveals a Tendency for Overestimation in Specimens with an N/C Ratio Approaching 0.5.

In the Paris System (TPS), standardized cytomorphological criteria and diagnostic categories were proposed for reporting urine cytology. To evaluate the diagnostic agreement and interobserver concordance for assessing TPS criteria, the Taiwan Society of Clinical Cytology organized an online survey with 10 atypical urine cytology cases. A total of 137 participants completed the survey. The mean agreement of diagnosis was 51.2%, ranging from 34.3% to 83.2% for each case. For 60% (6/10) of cases, the agreement was <50%. The interobserver concordance of diagnosis and cytological criteria assessment showed poor agreement. The nuclear-to-cytoplasmic (N/C) ratio had the highest kappa value of 0.386, indicating a significantly higher interobserver concordance and reproducibility than the other three TPS criteria. The correct rate of assessing the N/C ratio increased as the N/C ratio increased (correlation coefficient: 0.891, p < 0.01). Three cases with an N/C ratio near 0.5 were overestimated. Poor interobserver concordance of diagnosis and TPS criteria was revealed. Compared with other cytological features, the N/C ratio assessment was quantitative and more reproducible, but a tendency to overestimate cells was noted when the N/C ratio was approximately 0.5. Continuing education programs should emphasize the accurate assessment of N/C ratio to improve the application of TPS.

Intractable small-bowel obstruction due to urothelial cell carcinoma metastasis to the distal ileum: A rare cause of malignant bowel obstruction

Most patients with partial intestinal obstruction can be managed without surgical intervention. Here, we report the case of a patient who presented with partial intestinal obstruction. He had been diagnosed with high-grade urothelial cell carcinoma (UCC) 1.5 years previously, for which the surgery and adjuvant chemotherapy had been successfully performed. He showed a poor response to medical treatment for the partial intestinal obstruction, and surgery provided only a short-term benefit. Such cases of intractable small-bowel obstruction are infrequent and pose a challenge to clinicians. Although very rare, the possibility of UCC metastasis to the gastrointestinal tract should be considered in the differential diagnosis of refractory intestinal obstruction and history of UCC.

Vulvar Paget disease secondary to high-grade urothelial carcinoma with underlying massive vascular embolization and cervical involvement: case report of unusual presentation

BackgroundVulvar extramammary Paget disease is a rare chronic condition, that presents with non-specific symptoms such as pruritus and eczematous lesions. Because most of these lesions are noninvasive, the distinction between primary and secondary Paget disease is crucial to management.Case presentationWe report an unusual case of vulvar Paget disease associated with massive dermal vascular embolization, cervicovaginal involvement and metastasis to inguinal and retroperitoneal lymph nodes. The intraepithelial vulvar lesion had a classical appearance and was accompanied by extensive component of dermal lymphovascular tumor emboli, similar to those observed in inflammatory breast carcinoma. Immunohistochemical analysis revealed that the lesion was secondary to high-grade urothelial cell carcinoma. The patient had a history of superficial low-grade papillary urothelial carcinoma of the bladder, which had appeared 2 years before the onset of vulvar symptoms.ConclusionsEczematoid vulvar lesions merit careful clinical examination and biopsy, including vulva mapping and immunohistochemistry. The information obtained may help to define and classify a particular presentation of Paget disease. Noninvasive primary lesions do not require the same aggressive approaches required for the treatment of invasive and secondary disease.

Patient-derived Orthotopic Xenograft Models for Human Urothelial Cell Carcinoma and Colorectal Cancer Tumor Growth and Spontaneous Metastasis.

Cancer patients have poor prognoses when lymph node (LN) involvement is present in both high-grade urothelial cell carcinoma (HG-UCC) of the bladder and colorectal cancer (CRC). More than 50% of patients with muscle-invasive UCC, despite curative therapy for clinically-localized disease, will develop metastases and die within 5 years, and metastatic CRC is a leading cause of cancer-related deaths in the US. Xenograft models that consistently mimic UCC and CRC metastasis seen in patients are needed. This study aims to generate patient-derived orthotopic xenograft (PDOX) models of UCC and CRC for primary tumor growth and spontaneous metastases under the influence of LN stromal cells mimicking the progression of human metastatic diseases for drug screening. Fresh UCC and CRC tumors were obtained from consented patients undergoing resection for HG-UCC and colorectal adenocarcinoma, respectively. Co-inoculated with LN stromal cell (LNSC) analog HK cells, luciferase-tagged UCC cells were intra-vesically (IB) instilled into female non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice, and CRC cells were intra-rectally (IR) injected into male NOD/SCID mice. Tumor growth and metastasis were monitored weekly using bioluminescence imaging (BLI). Upon sacrifice, primary tumors and mouse organs were harvested, weighed, and formalin-fixed for Hematoxylin and Eosin and immunohistochemistry staining. In our unique PDOX models, xenograft tumors resemble patient pre-implantation tumors. In the presence of HK cells, both models have high tumor implantation rates measured by BLI and tumor weights, 83.3% for UCC and 96.9% for CRC, and high distant organ metastasis rates (33.3% detected liver or lung metastasis for UCC and 53.1% for CRC). In addition, both models have zero mortality from the procedure. We have established unique, reproducible PDOX models for human HG-UCC and CRC, which allow for tumor formation, growth, and metastasis studies. With these models, testing of novel therapeutic drugs can be performed efficiently and in a clinically-mimetic manner.

A patient-derived orthotopic xenograft model enabling human high-grade urothelial cell carcinoma of the bladder tumor implantation, growth, angiogenesis, and metastasis

High-grade urothelial cell carcinoma of the bladder has a poor prognosis when lymph nodes are involved. Despite curative therapy for clinically-localized disease, over half of the muscle-invasive urothelial cell carcinoma patients will develop metastases and die within 5 years. There are currently no described xenograft models that consistently mimic urothelial cell carcinoma metastasis. To develop a patient-derived orthotopic xenograft model to mimic clinical urothelial cell carcinoma progression to metastatic disease, the urothelial cell carcinoma cell line UM-UC-3 and two urothelial cell carcinoma patient specimens were doubly tagged with Luciferase/RFP and were intra-vesically (IB) instilled into NOD/SCID mice with or without lymph node stromal cells (HK cells). Mice were monitored weekly with bioluminescence imaging to assess tumor growth and metastasis. Primary tumors and organs were harvested for bioluminescence imaging, weight, and formalin-fixed for hematoxylin and eosin and immunohistochemistry staining. In this patient-derived orthotopic xenograft model, xenograft tumors showed better implantation rates than currently reported using other models. Xenograft tumors histologically resembled pre-implanted primary specimens from patients, presenting muscle-invasive growth patterns. In the presence of HK cells, tumor formation, tumor angiogenesis, and distant organ metastasis were significantly enhanced in both UM-UC-3 cells and patient-derived specimens. Thus, we established a unique, reproducible patient-derived orthotopic xenograft model using human high-grade urothelial cell carcinoma cells and lymph node stromal cells. It allows for investigating the mechanism involved in tumor formation and metastasis, and therefore it is useful for future testing the optimal sequence of conventional drugs or the efficacy of novel therapeutic drugs.

PD-L1 expression in tumor cells and the immunologic milieu of bladder carcinomas: a pathologic review of 165 cases

Programmed death ligand 1 (PD-L1) is a transmembrane protein that plays a major role in immune suppression. Its interaction with the receptor PD-1 results in downregulation of antitumoral immunity. Humanized monoclonal antibodies that interrupt the PD-L1/PD-1 interaction have shown therapeutic efficacy in patients with advanced urothelial cancer. However, immunohistochemical staining of PD-L1 in bladder tumors and its relationship to tumor histologic type, grade, and overall survival has been incompletely analyzed. Slides from 165 cystectomy specimens were reviewed for tumor type, grade of urothelial carcinoma, pathologic stage, and overall survival. A tissue microarray (TMA) using four 0.6 mm cores from each case was constructed. Immunohistochemistry was performed on the TMA using a variety of new PD-L1 antibodies and platforms now widely available. For each case, the percent of tumor cells positive for PD-L1 and the percent of positive immune cells were scored. The overall number of bladder cancers positive for PD-L1 depended on the antibody/platform combination used and the threshold for considering a tumor "PD-L1-positive." Squamous cell carcinomas (SCCs) of the bladder demonstrated PD-L1 positivity more frequently than urothelial cell carcinomas (UCCs). High-grade UCCs were positive for PD-L1 on tumor cells more frequently than low-grade UCCs. There was no difference in survival between PD-L1-positive and PD-L1-negative bladder cancers in our study. Further studies should consider examining the predictive significance of PD-L1 IHC in bladder cancers.

Diagnostic Accuracy of Qualitative and Quantitative Computed Tomography Analysis for Diagnosis of Pathological Grade and Stage in Upper Tract Urothelial Cell Carcinoma

The aim of this study was to compare grade and stage of upper tract urothelial cell carcinoma (UCC) using computed tomography. With institutional review board approval, 48 patients with 49 UCC (44 high grade and 5 low grade, 26 ≤ T1 and 23 ≥ T2) underwent nephroureterectomy and preoperative computed tomography between 2013 and 2015. Two blinded radiologists assessed for tumor appearance (filling defect/mass or wall thickening/stricture), margin (smooth or spiculated/irregular), texture (homogeneous, heterogeneous), hydronephrosis, and calcification. A third blinded radiologist established consensus. A fourth blinded radiologist measured size and first-order histogram texture features. Comparisons were performed using χ test, multivariable logistic regression, and receiver operator characteristic analysis. There was no difference in size of tumors compared by grade or stage (P = 0.80 and 0.13, respectively).Among subjective variables, only tumor texture was significantly different between low- and high-grade UCC (P = 0.03; κ = 0.45). Tumors characterized as spiculated/irregular margin (P = 0.003; 0.30) and heterogeneous (P < 0.001; κ = 0.45) were associated with T2 disease or higher.Entropy was greater in higher grade (6.23 ± 0.46 vs 5.72 ± 0.28) and T2 disease or higher (6.40 ± 0.33 vs 5.95 ± 0.48), (P = 0.03 and 0.02, respectively) with no differences in Kurtosis or Skewness (P > 0.05). Area under the receiver operator characteristic curve for entropy to diagnose high-grade and T2 tumors or higher was 0.83 (confidence interval, 0.64-1.0) and 0.79 (confidence interval 0.59-0.98), respectively. Heterogeneity, assessed qualitatively and quantitatively, is accurate for diagnosis of higher grade and stage of disease in upper tract UCC. Spiculated/irregular margins are also associated with T2 disease or higher.

ANALYSIS OF THE EXPRESSION OF FAS/CD95 AND HSP70 IN LOW AND HIGH GRADE UROTHELIAL CELL CARCINOMA OF THE BLADDER

Urothelial Cell Carcinoma (UCC), also called transitional cell carcinoma of the bladder, is the most common malignancy in urinary tract. The prognosis of this disease is highly dependent on the histological grading at diagnosis. Fas/CD95 has a role in apoptotic process, whereas HSP70 has an antiapoptotic role. This study aimed to analyze the expression of Fas/CD95 and HSP70 in low grade and high grade urothelial cell carcinoma in the bladder. This was an analytic observational study with cross sectional approach. Population and sample were paraffin blocks of urothelial cell carcinoma in the Laboratory of Anatomic Pathology, Dr. Soetomo Hospital, Surabaya in the period of January 2011-December 2016. Each grading of urothelial cell carcinoma was randomly sampled. Immunohistochemystry with Fas/CD95 and HSP70 were performed. Expression of Fas/CD95 and HSP70 were assessed semiquantitatively. Expression of Fas/CD95 and HSP70 were analyzed using Mann-Whitney test and Spearman test. The results showed there was significant different in expression of Fas/CD95 and HSP70 in low and high grades in urothelial cell carcinoma. There was no significant correlation between the expression of Fas/CD95 and HSP70 in urothelial cell carcinoma. As a conclusion, the role of CD95 and HSP70 expression can be useful as marker for the diagnosis, especially in the determination of the grade of differentiation.

Port-site metastasis as a primary complication following retroperitoneal laparoscopic radical resection of renal pelvis carcinoma or nephron-sparing surgery: A report of three cases and review of the literature.

The present study reports the clinical data of two patients with renal pelvis carcinoma and one patient with renal carcinoma who developed port-site metastasis following retroperitoneal laparoscopic surgery. The current study aimed to identify the cause and prognosis of the occurrence of port-site metastasis subsequent to laparoscopic radical resection of renal pelvis carcinoma and nephron-sparing surgery. Post-operative pathology confirmed the presence of high-grade urothelial cell carcinoma in two patients and Fuhrman grade 3 renal clear cell carcinoma in one patient. Port-site metastasis was initially detected 1–7 months post-surgery. The two patients with renal pelvis carcinoma succumbed to the disease 2 and 4 months following the identification of the port-site metastasis, respectively, whereas the patient with renal carcinoma survived with no disease progression during the targeted therapy period. The occurrence of port-site metastasis may be attributed to systemic and local factors. Measures to reduce the development of this complication include strict compliance with the operating guidelines for tumor surgery, avoidance of air leakage at the port-site, complete removal of the specimen with an impermeable bag, irrigation of the laparoscopic instruments and incisional wound with povidone-iodine when necessary, and enhancement of the body's immunity. Close post-operative follow-up observation for signs of recurrence or metastasis is essential, and systemic chemotherapy may be required in patients with high-grade renal pelvis carcinoma and renal carcinoma in order to prolong life expectancy.

Higher Expression of miR-182 in Cytology Specimens of High-Grade Urothelial Cell Carcinoma: A Potential Diagnostic Marker

Objective: MicroRNAs (miRs) are short noncoding RNA molecules that posttranscriptionally modulate protein expression. There are distinct miR alterations characterizing urothelial cell carcinoma (UCC) of the urinary bladder. Study Design: In this study, we investigate the possibility of using miR as a noninvasive marker in the screening of UCC. The total RNA was extracted from 75 cytology specimens including bladder or renal washings and voided urines. Cases comprise UCC (21 high grade and 6 low grade), 25 normal controls and 23 cases with a history of UCC but negative at the time of testing (negative with a positive history). The expressions of miR-96, miR-182, miR-183, miR-200c, miR-21, miR-141 and miR-30b were determined using quantitative TaqMan real-time PCR. Results and Conclusion: This study shows that the level of miR-182 is higher in cytology specimens from high-grade UCC patients as compared to normal controls. Measuring miR-182 may provide a potential alternative or adjunct approach for screening high-grade UCC.

CEUS in the study of bladder, method, administration and evaluation, a technical note

Contrast-enhanced ultrasound (CEUS) is the application of ultrasound contrast agents (UCAs) to traditional medical sonography. The development of UCAs allowed to overcome some of the limitations of conventional B-mode and Doppler ultrasound techniques and enabled the display of the parenchymal microvasculature. Purpose of this paper is to delineate the elements of a solid and science-based technique in the execution of urinary bladder CEUS. We describe the technical execution of urinary bladder CEUS and the use of perfusion softwares to perform contrast enhancement quantitative analysis with generation of time-intensity curves from regions of interest. During CEUS, normal bladder wall shows a wash-in time of 13s, a time to peak (TTP) >40s, a signal intensity (SI) <45% and a wash-out time >80s; Low-grade urothelial cell carcinoma (UCC) shows a wash-in time of 13s, a time to peak TTP >28s, a SI <45% and a wash-out time of 40s; High-grade UCC shows a wash-in time of 13s, a TTP >28s, a SI >50% and a wash-out time of 58s. CEUS is a useful tool for an accurate characterization of bladder UCC although it has some drawbacks. To avoid misunderstandings, a widely accepted classification and a standardized terminology about the most significant parameters of this application should be adopted in the immediate future.

Evaluation of urovysion and cytology for bladder cancer detection

Urine cytology has been used for screening of bladder cancer but has been limited by its low sensitivity. UroVysion is a multiprobe fluorescence in situ hybridization (FISH) assay that detects common chromosome abnormalities in bladder cancers. For this study, the authors evaluated the effectiveness of multiprobe FISH and urine cytology in detecting urothelial cell carcinoma (UCC) in the same urine sample. In total, 1835 cases with the following criteria were selected: valid results from both the multiprobe FISH assay and urine cytology in the same urine sample, histologic and/or cystoscopic follow-up within 4 months of the original tests, or at least 3 years of clinical follow-up information. The results of FISH and cytology were correlated with clinical outcomes derived from a combination of histologic, cystoscopic, and clinical follow-up information. Of 1835 cases, 1045 cases were from patients undergoing surveillance of recurrent UCC, and 790 were for hematuria. The overall sensitivity, specificity, positive predictive value, and negative predictive value in detecting UCC were 61.9%, 89.7%, 53.9%, and 92.4%, respectively, for FISH and 29.1%, 96.9%, 64.4%, and 87.5%, respectively, for cytology. The performance of both FISH and cytology generally was better in the surveillance population and in samples with high-grade UCC. In 95 of 296 cases with atypical cytology that were proven to have UCC, 61 cases, mostly high-grade UCC, were positive using the multiprobe FISH assay. The UroVysion multiprobe FISH assay was more sensitive than urine cytology in detecting UCC, but it produced more false-positive results. The current data suggest that the use of FISH as a reflex test after an equivocal cytologic diagnosis may play an effective role in detecting UCC.

A Case of Concomitant Occurrence of Solitary Fibrous Tumor and Urothelial High-Grade Invasive Carcinoma of the Urinary Bladder

Solitary fibrous tumor (SFT) is a rare mesenchymal neoplasm, most commonly arising from the pleura. It has also been recently described to occur in extrapleural sites. To our knowledge, only 16 cases of SFT have been reported in the urinary bladder to date. We report the clinicopathological features of a vesical SFT occurring in a 60-year-old man who presented a concomitant invasive high-grade urothelial cell carcinoma. No similar association has been found in the accessible literature. The morphologic and immunohistochemical clues leading to the correct diagnosis of SFT have been correlated with the data of the literature, and the differential diagnosis is briefly discussed.

Abstract LB-450: Necrosis predicts benefit from hypoxia-modifying therapy in urothelial cell carcinoma of the bladder

Abstract To investigate the ability of tumor necrosis to predict benefit following radiotherapy with and without hypoxia-modifying treatment in high grade urothelial cell carcinoma of the urinary bladder. Background: There is no predictive marker of hypoxia-modifying therapy in cancer patients in routine clinical use. Methods: We identified 231 patients who participated in the BCON phase III randomised trial comparing radical radiotherapy (RT) with and without carbogen and nicotinamide (CON) in patients with urothelial cell carcinoma of the bladder who were suitable for this retrospective study. Tumor necrosis was scored on whole tissue sections as absent or present. Results: Tumor necrosis was identified in 121 of the 231 patients (52%). 5-year overall survival estimates were 41% for the RT arm and 48% for the CON arm (log rank p=0.14). When stratified using tumor necrosis, the 5-year overall survival estimates were 48% (RT) and 39% (CON) (log rank p =0.32) in patients with no evident tumor necrosis, and 34% (RT) and 56% (CON) (log rank p=0.004) in patients with tumor necrosis. Multivariate analyses showed that the presence of tumor necrosis was a significant predictor of benefit from CON with the risk of dying 57% lower compared to RT alone (HR 0.43, 95% CI 0.25-0.73, p=0.002). This trend was not observed when there is no evident tumour necrosis (HR 1.64, 95% CI 0.95-2.85, p=0.08). Test for heterogeneity in treatment effect by necrosis strata (p=0.007 unadjusted, p=0.001 adjusted). Conclusions: Tumor necrosis significantly predicts benefit from radiotherapy with hypoxia-modifying treatment. Independent validation in a prospective trial is warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-450. doi:1538-7445.AM2012-LB-450

Patterns of autophagy in urothelial cell carcinomas—the significance of “stone-like” structures (SLS) in transurethral resection biopsies

ObjectivesTo investigate the microtubule-associated protein LC3A, presumed to reflect autophagic activity, in urothelial cell carcinomas (UCC) for its relevance with muscle invasion in transurethral resection (TUR) biopsies. The LC3A antibody is specific for identifying the autophagy-related protein Atg8 and, hence, autophagy—a self-degradation mechanism by which cells recycle their own cytoplasmic constituents, providing with additional energy the rapidly proliferating cells. MethodsThe study comprised 210 TUR specimens of UCC of the urinary bladder: 70 low-grade non-muscle-invasive (NMI, group A), 70 high-grade NMI (group B), and 70 high-grade muscle invasive tumors (group C). These, together with 40 controls, were stained for Atg8/LC3 using an automated immunohistochemical technique. ResultsThe LC3A was detected as diffuse cytoplasmic staining, and as dense, spheroidal, “stone-like” structures (SLS) of variable size (1.2–12.0 μm in diameter), typically enclosed within cytoplasmic vacuoles. The LC3A reactivity, whether expressed in the form of SLS or as diffuse cytoplasmic staining, was higher in high-grade UCC than in low-grade disease and, more importantly, it was associated with muscle invasion. The median number of SLS per optical field, per section was 17.0, 19.0, and 37.0 for groups A, B, and C, respectively (A, B vs. C P < 178> 0.0001; A vs. B P = 0.27). The median SLS diameter was 4.9, 5.3, and 9.3 μm for groups A, B, and C respectively (A, B, vs. C P < 0.0001; A vs. B P = 0.03). ConclusionIt appears that the LC3A protein is closely connected with muscle invasion, but whether this finding is of clinical value in TUR specimens lacking muscularis propria remains to be proven.

Immunohistochemical Profile of Urothelial and Small Cell Carcinomas of the Bladder

Small cell carcinoma of the bladder is an uncommon and rather aggressive bladder tumor, representing less than 1% of all vesical tumors. Small cell carcinoma of different organs has been shown to express markers of neuroendocrine differentiation, and also thyroid transcription factor 1 (TTF-1). TTF-1 is a transcription factor and its expression has been shown mainly in pulmonary small cell carcinomas and adenocarcinomas and in thyroid tumors. Although it was initially proposed as a useful marker to delineate the origin of metastatic adenocarcinomas from the lung, its expression is being increasingly reported in tumors from different origins. The goal of this review is to analyse the immunohistochemical profile of small cell carcinoma of the bladder and to compare it to classical urothelial cell carcinomas. With this aim we have reviewed the small cell bladder carcinomas diagnosed in a single tertiary hospital in Madrid (Fundación Jiménez Díaz) in the last 12years. We have found 6 pure small cell carcinomas and performed a wide panel of immunohistochemistry, including cytokeratins 7 and 20, enolase, chromogranin, synaptophysin, CD56 and TTF-1 to these tumors and also to 30 high grade urothelial cell carcinomas of usual type. Only one of our small cell carcinoma cases showed positivity for TTF-1, while five expressed CD56 and four neuron-specific enolase. None of our cases expressed cytokeratin 20 or 7. To our surprise we found a case of conventional urothelial cell carcinoma expressing focally TTF-1. These results are in accordance with the current literature, although our rate of TTF-1 expression (16.6%) is on the low end of the spectrum.