Low-grade Transitional Cell Carcinoma Research Articles

401 Three Birds with One Stone: Ureteric Calculus Precipitates Diagnosis and Resection of Three Primary Neoplasms

Abstract A 67 year-old female presented to our centre with a 2 day history of right flank pain, clinically suggestive of ureteric colic. Computed tomography (CT) confirmed a 6mm right ureteric calculus. However, CT also revealed a large 13cm ipsilateral renal mass, concerning for renal cell carcinoma (RCC). At ureteroscopy for management of the obstructing calculus, a small papillary lesion was noted in the bladder, and excised. Histology confirmed pTa low-grade transitional cell carcinoma. Following discussion at the Urology multidisciplinary tumour board, MRI venogram (MRV) was recommended to delineate the extension of tumour into the renal vein, and to characterise a pelvic mass seen on original CT. MRV showed enhancing material extending into the IVC, consistent with tumour thrombus. However, it also identified a concerning 6cm solid ovarian mass. The patient proceeded to open right radical nephrectomy and IVC thrombectomy, hysterectomy, bilateral salpingo-oopherectomy, and omental biopsy, with combined input from Urological, Gynaecological and Vascular surgical teams. Post-operative course was uneventful. Histology showed an 11cm pT3a G2 clear cell RCC, and 7.5cm ovarian fibroma, both fully excised. This case demonstrated the serendipity of a simple ureteric calculus precipitating a cascade of investigations, that ultimately led to complete resection of three primary neoplasms.

Evaluation of the Role of Early Second Look Cystoscopy after Complete Resection of Non-Muscle Invasive Bladder Tumors

Abstract Background most of the bladder cancers are non-muscle invasion at the time of diagnosis. Non-Muscle invasive tumors confined to the mucosa and invading the lamina propria are classified as stage Ta and T1, respectively, according to the Tumor, Node, Metastasis (TNM) classification system. Aim of the Study to determine the efficacy of early second look cystoscopy after complete resection of non-muscle invasive urinary bladder tumors and its impact on subsequent treatment policy. Patients and Methods this is a prospective clinical study that was done at Urology Department, Faculty of Medicine, Ain Shams University and Damanhur Oncology Centre. A total of 40 consecutive patients with newly diagnosed non-muscle invasive bladder cancer will be enrolled in this prospective study for second-look cystoscopy with TURBT in two to six weeks after initial TURBT and follow them up in one year. Results Single tumor was found in 22 cases (55%), while multiple tumors were recognized in 18 cases (45%) with average sizes ranging from 12mm to 70mm. Low-grade transitional cell carcinoma (TCC) was found in 26 cases (65%), whereas high-grade TCC was found in 14 cases (35%). Stage PTa tumors was found in 12 cases (30%) while 28 cases (70%) have had tumors of PT1 stage. All cases underwent an early second TURBT after (2-6) weeks which has reviled the following data. The majority of cases (28 cases) representing 70% of whole study population were free with no detection of any tumors either residual or recurrence. Residual tumors were detected in six cases (15%) all of which detected in patient with large primary tumor size exceeding 50mm or patients with multiple tumors. Whole detected residual tumors were found at edges of primary tumors ranging 2-5 mm in size which were completely resected and they were of the same stage and grade as the initial tumor. Conclusion Our findings in this study support the notion that second-look cystoscopy with or without TURBT is a prerequisite in patients with superficial bladder cancers except for patients with solitary, small low-grade pTa tumors. It is particularly highly recommended for patients with extensive and multiple tumors at the first TURBT

Adaptive genetic algorithms combined with high sensitivity single cell-based technology derived urine-based score to differentiate between high-grade and low-grade transitional cell carcinoma of the bladder.

572 Background: We previously showed that adaptive genetic algorithms (AGA), in combination with single-cell flow cytometry technology, can be used to develop a noninvasive urine-based score to detect bladder cancer with high accuracy. Our aim in this analysis was to investigate if that same score can differentiate between high grade (HG) and low grade (LG) transitional cell carcinoma of the bladder (BC). Methods: We collected urine samples from cystoscopy confirmed HG and LG superficial bladder cancer patients and healthy donors in an optimized urine collection media. We then examined these samples using an assay developed from AGA in combination with single-cell flow cytometry technology. Results: We examined 50 BC and 15 healthy donor urine samples. Patients were majorly White (59.2%), males (61.2%), and had HG BC (66.7%). AGA derived score of 1.1 differentiated between BCa and healthy patients with high precision (AUC 0.92). The median score was 2.8 for LG BC and 6 for LG BC. Mann-Whitney Rank Sum Test indicated that the difference between the median score of HG and LG BC was significant at P value = 0.003. The score performed well independent of patients’ sex or smoking history. Conclusions: Using single-cell technology and machine learning, we developed a new urine-based score that can potentially differentiate between HG and LG bladder cancer. Future studies are planned to validate this score.

Low grade transitional cell carcinoma of the urethra successfully treated with only intraurethral instillation of Mitomycin-C

Urethral cancer is very rare disease, accounting for less than 0.5% of incidences of malignancies. Data on its management are scarce due to the rare nature of the cases. We present a 34-year-old man, who presented to our hospital with a month history of hematuria. He had no lower urinary tract symptoms and no significant risk factors for urothelial cancer. He was evaluated and found to have lesions in the posterior urethra on urethrocytoscopy, biopsy of which revealed a low-grade urothelial cancer. He was counselled and had 6 courses of intraurethral instillation of 40mg of Mitomycin-C diluited in 50mL of saline held in the urethra with penile clamp for 30 minutes. The hematuria stopped after the second course, a repeat urethrocystoscopy 6 months after the completion of the chemotherapy, showed resolution of the lesion and repeat biopsy showed no evidence of malignancy. However, the patient developed short segment partial penile urethral stricture that was treated with dilatation. In conclusion, low-grade urothelial cancer of the urethra can be successfully cured with Intraurethral instillation of Mitomycin-C, without prior transurethral resection.

Histopathological Spectrum of Bladder Lesions : Our Observation in 128 Cystoscopic Specimen

Background : Diseases of the bladder, particularly, inflammation (Cystitis), constitutes an important source of clinical signs & symptoms. Tumours of the bladder are an important source of both morbidity and mortality. The aim of the study was to make a histopathological evaluation of various bladder lesions and to observe the frequency of different bladder lesions. Material and methods : The study was conducted in the Department of Pathology, Chittagong Maa-O-Shishu Hospital Medical College (CMOSHMC) from Jan 2012 to Dec 2016. Patients particulars and histopathological diagnosis were kept in records. Tissue was processed in paraffin section technique and stained with routine Hematoxilin and eosin stains. Results : One hundred and twenty eight (128) cystoscopic sample were studied. Out of 128 cases males were 103 and 25 were females with a male to female ratio of 4.21:1. In malignant lesions the male to female ratio was 3.82:1. Age distribution ranges from 13 to 85 years with an average age of 57 years. The maximum age group belonged to 51 to 60 years and 61 to 70 years. The spectrum of lesions included non neoplastic and neoplastic lesions. Non neoplastic lesions were eosinophilic cystitis, granulomatous cystitis, radiation induced cystitis, chronic follicular cystitis and cystitis gladularis etc. The neoplastic lesions were, transitional cell papilloma, Papillary Urothelial Neoplasm of Low Malignant Potential (PUNLMP) low and high grade Transitional Cell Carcinoma (TCC) and leiomyosarcoma. Low grade TCC was the predominant type. Conclusion : Cystoscopic biopsy followed by histopatholigical examination is essential to diagnose any organic bladder lesion for proper management. Smooth muscle should be included in biopsy whenever malignancy is suspected.
 JCMCTA 2017 ; 28 (1) : 42 - 44

Preliminary study on the expression of Toll-like receptors 7 and 8 in bladder urothelial tumors

The aim of the study was to demonstrate the expression of Toll-like receptor (TLR)-8 and to confirm the expression of TLR-7 on bladder transitional cell carcinomas (TCCs) analyzing the changes in expression between low-grade (LG) and high-grade (HG) and between non-muscle invasive (NMIBC) and muscle-invasive (MIBC) bladder cancers. In our study, 25 patients who underwent transurethral resection (TURB) for bladder TCC have been selected. Thirteen of those had an LG form,while the other cases were classified as HG; the lesions were NMIBC in 18 patients and MIBC in the others seven. The analysis of TLRs expression has been performed by immuno histochemistry. TRL-8 expression seems to be higher in MIBC (85%) than in NMIBC (78%), but it is associated with a reduced percentage of immuno reactive cells and with a lower intensity. The expression had a large nuclear localization in NMIBC (80%), althoughit was mainly cytoplasmic in MIBC (72%). TLR-7 was expressed in all NMIBC samples (where the localization was mainly nucleo-cytoplasmic) and in the 71% of MIBC samples (mainly in the nucleus). A higher expression of TRL-8 in HG TCC had been observed, while TRL-7 seems to be more expressed in LG forms. Our study allowed to document the immunohistochemical expression of TLR-8 in TCCs, confirm the immunohistochemical expression of TLR-7, and suggest an increased expression of TLR-7 in LG TCC and NMIBC, and a prevalent expression of TLR-8 in HG TCC and MIBC.

Cystoscopy in children presenting with hematuria should not be overlooked

A 14-year-old girl was admitted with the complaints of intermittent painless macroscopic hematuria the ongoing for nearly two months and dysuria. Ten to 15 erythrocytes and plenty of urine leukocytes were found in the investigation. Ultrasonographic examination of the posterior wall of the bladder showed that a polypoid hypoechoic solid lesion 28 x 11 mm in size was protruding into the lumen. Cystoscopy showed a vegetating papillary tumor of 2x3 cm in size on the posterior wall of the bladder protruding into the lumen; this was then resected. Histopathological examination showed low-grade (G1) transitional cell carcinoma. In the light of this case, in children presenting with hematuria, the possibility of bladder tumors should be kept in mind; thus, retraction with the help of a cystoscope should be considered.

High-Grade Non-Invasive Transitional Cell Carcinoma with Osseous Metaplasia of the 3-Year-Old Boy Urinary Bladder

Transitional cell carcinomas of the urinary bladder are very rare in paediatrics. In children clearly outweights low grade transitional cell carcinomas, however individual cases of high grade tumors were also described.

Bladder tumours in children: An interesting case report of TCC with a partial inverted growth pattern.

Bladder urothelial carcinoma is typically a disease of older individuals and rarely occurs below the age of 40 years. There is debate and uncertainty in the literature regarding the clinicopathologic and prognostic characteristics of bladder urothelial neoplasms in younger patients compared with older patients, although no consistent age criteria have been used to define "younger" age group categories. We report on a 16 years old girl with transitional cell carcinoma of the bladder with a partial inverted growth pattern who presented with gross hematuria. Ultrasonography revealed a papillary lesion in the bladder; cystoscopic evaluation showed a 15 mm papillary lesion with a thick stalk located in the left bladder wall. Pathologic evaluation of the specimen was reported as "low grade transitional cell carcinoma of the bladder with a partial inverted growth pattern".

Cystic pulmonary lesions in a case of bladder tumor

Metastases are rarely seen in cases of low grade transitional cell carcinoma of urinary bladder. The most common sites of distant metastasis are the liver, lung, mediastinum and bones. Pulmonary metastases from transitional cell carcinoma usually present as multiple nodules, solitary mass or interstitial micronodules and rarely manifests as cystic pulmonary lesions. We present an unusual case of cystic pulmonary nodules diagnosed to be metastases from transitional cell carcinoma of the urinary bladder. We conclude that in a known case of transitional cell carcinoma of urinary bladder, if presenting with cystic lesion in the lung parenchyma, metastasis should be considered among differential diagnosis along with more common causes.

TERT promoter mutations occur early in urothelial neoplasia and are biomarkers of early disease and disease recurrence in urine.

Activating mutations occur in the promoter of the telomerase reverse transcriptase (TERT) gene in 66% of muscle-invasive urothelial carcinomas. To explore their role in bladder cancer development and to assess their utility as urine markers for early detection, we sequenced the TERT promoter in 76 well-characterized papillary and flat noninvasive urothelial carcinomas, including 28 pTa low-grade transitional cell carcinomas (TCC), 31 pTa high-grade TCCs, and 17 pTis carcinoma in situ lesions. We also evaluated the sequence of the TERT promoter in a separate series of 14 early bladder neoplasms and matched follow-up urine samples to determine whether urine TERT status was an indicator of disease recurrence. A high rate of TERT promoter mutation was observed in both papillary and flat lesions, as well as in low- and high-grade noninvasive urothelial neoplasms (mean: 74%). In addition, among patients whose tumors harbored TERT promoter mutations, the same mutations were present in follow-up urines in seven of eight patients that recurred but in none of the six patients that did not recur (P < 0.001). TERT promoter mutations occur in both papillary and flat lesions, are the most frequent genetic alterations identified to date in noninvasive precursor lesions of the bladder, are detectable in urine, and seem to be strongly associated with bladder cancer recurrence. These provocative results suggest that TERT promoter mutations may offer a useful urinary biomarker for both early detection and monitoring of bladder neoplasia.

The Lin28/let-7a/c-Myc pathway plays a role in non-muscle invasive bladder cancer

We investigate the role of the Lin28/let-7a/c-Myc pathway in non-muscle invasive bladder cancer (NMIBC). Using RT-PCR, western blot and immunohistochemistry techniques, the levels of pre-let-7a, let-7a, Lin28 and c-Myc RNA and/or proteins were determined in samples of normal bladder tissue and bladder cancer. Expression of pre-let-7a was found to be negatively correlated with the pathological grade of bladder cancer, while let-7a showed a positive correlation with bladder cancer pathological grade. Expression of Lin28 RNA and protein was not significantly different between normal bladder tissue and low-grade transitional cell carcinoma of bladder (TCC) but the expression levels in high-grade TCC were remarkably increased. Expression of c-Myc RNA and protein was significantly higher in bladder cancer samples in comparison to normal bladder tissue without correlation with cancer differentiation. Expression of all the above RNAs and proteins showed no significant difference in Ta and T1 stages. The Lin28/let-7a/c-Myc pathway plays an important role in NMIBC. In particular, expression levels of let-7a correlate with the degree of cancer differentiation but not cancer stage.

Comparison of Urinary and Serum CA 19-9 as Markers of Early Stage Urothelial Carcinoma

Although the glycoprotein group tumor marker CA 19-9 has been detected in both serum and urine of bladder cancer patients, information about their comparative role in screening of low grade transitional cell carcinoma (LGTCC) and high grade transitional cell carcinoma (HGTCC) is rare. In this study we measured both the urinary and serum levels of CA 19-9 in 35 LGTCC and 20 HGTCC patients by ELISA and determined the cut off value of both urinary and serum CA 19-9 levels by receiver operator characteristic curve (ROC) for both patient groups. Odds ratio (OR) for CA 19-9 was analyzed with its range at 95% confidence interval to analyze the role of this tumor marker as a screening parameter for both of these cancer types. For urinary CA 19-9 the OR was 20.16 with an interval of 4.91-82.71 whereas for the serum CA 19-9 it was 7.5 with an interval of 2.28-24.62. From these data we suggest that urinary CA 19-9 is a better screening parameter with optimum sensitivity and specificity than its serum counterpart for diagnosis of low grade and early stages of transitional cell carcinoma of urinary bladder. Furthermore, it can be suggested that urinary CA 19-9 can be used as better prognostic marker for LGTCC than its serum counterpart.

Intravesical and transperitoneal laparoscopy in the management of tumor in the residual ureter

The occurrence of tumor in the residual ureter after an incomplete nephroureterectomy required by a tumor of renal collecting system is an uncommon but a well described situation. The recommended treatment in this situation is the radical excision of the remaining ureter, being the open technique the most used approach. The aim of this video is to demonstrate a new approach using intravesical and transperitoneal laparoscopy to remove the residual ureter following the oncological concepts. A 67 year-old male patient underwent an incomplete open right radical nephroureterectomy for a transitional cell carcinoma of the renal collecting system. After 16 months, the cystoscopy diagnostic revealed a recurrence of it in the residual ureter. An intravesical approach followed by a transperitoneal laparoscopy has removed the remaining ureter. Operative time was 110 minutes, blood loss 100 mL, the patient was discharged on the first postoperative day and the Foley catheter was removed on the seventh one. Pathological examination revealed low grade transitional cell carcinoma and free surgical margins, no recurrence was observed after six months. To our knowledge, this is the first treatment description of a tumor in the residual ureter with these techniques. This approach can be a minimal invasive alternative in this unusual situation.

Gelatinous Marrow Transformation in an Imatinib-Treated CML Patient with Pancytopenia Following Severe Sepsis

Gelatinous Marrow Transformation in an Imatinib-Treated CML Patient with Pancytopenia Following Severe Sepsis

CIP2A protein expression in high‐grade, high‐stage bladder cancer

Bladder cancer is one of the most common cancers in the United States. Numerous markers have been evaluated for suitability of bladder cancer detection and surveillance. However, few of them are acceptable as a routine tool. Therefore, there exists a continuing need for an assay that detects the presence of bladder cancer in humans. It would be advantageous to develop an assay with a protein that is associated with the development of bladder cancer. We have identified the cancerous inhibitor of PP2A (CIP2A) protein as a novel bladder cancer biomarker. In this study, Western blot analysis was used to assess the expression level of CIP2A protein in bladder cancer cell lines and bladder cancer patient tissues (n = 43). Our studies indicated CIP2A protein was abundantly expressed in bladder cancer cell lines but not in nontumor epithelial cell lines. Furthermore, CIP2A was specifically expressed in transitional cell carcinoma (TCC) of the bladder tumor tissues but not in adjacent nontumor bladder tissue. Our data showed that CIP2A protein detection in high-grade TCC tissues had a sensitivity of 65%, which is 3.4-fold higher than that seen in low-grade TCC tissues (19%). The level of CIP2A protein expression increased with the stage of disease (12%, 27%, 67%, and 100% for pTa, pT1, pT2, and pT3 tumor, respectively). In conclusion, our studies suggest that CIP2A protein is specifically expressed in human bladder tumors. CIP2A is preferentially expressed in high-grade and high-stage TCC tumors, which are high-risk and invasive tumors. Our studies reported here support the role of CIP2A in bladder cancer progression and its usefulness for the surveillance of recurrence or progression of human bladder cancer.

Epigenetic regulation of vascular endothelial growth factor a dynamic expression in transitional cell carcinoma

Vascular endothelial growth factor A (VEGF-A) is a key mediator in the neovascularization of cancers. We have found that VEGF-A was expressed at significantly higher levels in high-grade transitional cell carcinoma (TCC) cells than low-grade TCC cells in our previous study. In the present study, promoter methylation pattern was assessed and quantified by bisulfite genomic sequencing (BGS) and specific VEGF-A CpG sites in low-grade, but not in high-grade, TCC cells were observed. Reporter assays indicated that hypermethylation of nine CpG sites can inhibit the transcriptional activity of the VEGF-A gene. Subsequent chromatin immunoprecipitation (ChIP) assay revealed down-regulation of transcription activity of VEGF-A with increasing binding of methyl-CpG-binding protein 2 (MBD2) and trimethyl-histone H3 (Lys9) proteins to these CpG sites in low-grade TCC cells during hypermethylation. Furthermore, treatment of low-grade TCC cells with DNA methyltransferase inhibitor and histone deacetylase inhibitor can restore the expression of VEGF-A and promote the invasive ability of low-grade TCC cells. Hypermethylation with lower expression levels of VEGF-A in low-grade TCC tumors than high-grade TCC tumors was also confirmed in clinical specimens by reverse transcriptase-PCR and pyrosequencing analyses. Our findings are the first results indicating that VEGF-A expression is suppressed in low-grade TCC tumors by promoter hypermethylation. This offers a new perspective on the role of VEGF-A in TCC tumor behavior.

The Relationship between Mast Cell Density and Tumour Grade in Transitional Cell Carcinoma of the Bladder

This study investigated the relationship between mast cell numbers and the grade of bladder transitional cell carcinoma (TCC). Bladder TCC biopsies were obtained via transurethral resection and 45 stage T1 specimens were included in the study. Specimens were sorted into two groups, low grade (grade I) and high grade (grades II and III). Samples were stained using haematoxylin and eosin, toluidine blue and immunohistochemical staining for tryptase. Mast cells were examined by light microscopy and cell density was recorded. Mast cell density was significantly higher in high-grade TCC than low-grade TCC. There was also a significant relationship between the number of mast cells identified using toluidine blue staining or immunohistochemical staining for tryptase. Detailed studies of mast cell function will enable the development of more effective antitumour therapies via mast cell manipulation.

7117 POSTER Claudins and Ki-67 – Potential Markers to Differentiate Low and High Grade Transitional Cell Carcinomas of the Urinary Bladder

7117 POSTER Claudins and Ki-67 – Potential Markers to Differentiate Low and High Grade Transitional Cell Carcinomas of the Urinary Bladder

Role of Low-Mechanical Index CEUS in the Differentiation between Low and High Grade Bladder Carcinoma: a Pilot Study

To assess the efficacy of low-mechanical index contrast-enhanced ultrasonography (CEUS) in the differentiation of a series of histologically proven bladder lesions identified via conventional cystoscopy and biopsied. 36 patients (mean age: 62 years; range 45 - 72 years) with bladder lesions previously detected by color power Doppler ultrasonography (CDUS) were prospectively examined with low-mechanical index contrast-enhanced US after bolus administration of 2.4 ml of Sonovue (Bracco, Milan, Italy). All lesions were evaluated in real-time continuous scanning for 2 minutes and the videos were registered. Two ultrasound (US) experts evaluated the videos by consensus and assigned a score to the enhancement pattern. Subsequently, a specific sonographic quantification software (Qontrast, Bracco, Milan, Italy) based on pixel by pixel signal intensity over time was used to obtain contrast-enhanced sonographic perfusion maps for each lesion. Time-intensity curves (TICs) of each lesion were then extracted from the region of interest positioned within the lesion and in the closest bladder wall. The sensitivity and specificity of CDUS and CEUS were compared using McNemar's test. All patients subsequently underwent conventional cystoscopy with biopsy or transurethral resection. 22 high-grade and 14 low-grade transitional cell carcinomas (TCCs) were histologically diagnosed (mean diameter 2.1 cm; range: 1 - 4.5 cm). The sensitivity and specificity of CDUS were 86.4% (19 / 22; 95% CI = 66.7 - 95.3%) and 42.9% (6 / 14; 95% CI = 21.4 - 67.4%), respectively. The sensitivity and specificity of CEUS were 90.9% (20 / 22; 95% CI = 72.2 - 97.5%) and 85.7% (12 / 14; 95% CI = 60.1 - 95.9%), respectively. The sensitivity and specificity of CEUS using TICs were 95.4% (21 / 22; 95% CI = 78.2 - 99.2%) and 85.7% (12 / 14; 95% CI = 60.1 - 95.9%), respectively. There was no significant difference between the sensitivity of CDUS versus CEUS, CDUS versus TIC, and CEUS versus TIC (p > 0.05; McNemar's test). The specificity of CEUS and TIC was significantly higher than that of CDUS (p < 0.05; McNemar test). CEUS is a reliable noninvasive method for differentiating low- and high-grade bladder carcinomas since it provides typical enhancement patterns as well as specific contrast-sonographic perfusion curves. However, further studies involving larger patient populations is mandatory to confirm these promising results.