FGFR3 mutations indicate better survival in invasive upper urinary tract and bladder tumours

Background

Promoter hypermethylation and microsatellite instability are frequent in tumours of the upper urinary tract (UTT) and infrequent in bladder tumours. FGFR3 mutations are common findings in bladder tumours and are associated with a good prognosis.

Objective

To investigate the occurrence of FGFR3 mutations in UTT and determine the prognostic effect of these genetic changes.

Design, setting, and participants

Tissue from the initial tumour was obtained from 280 patients (117 bladder tumours and 163 UTT). Patients were selected from pathologic archives to represent the disease spectrum of UCC throughout the urinary tract. Following UCC excision, patients underwent surveillance for a median of 56 mo (range 1–216 mo) or until death.

Measurements

FGFR3 mutation analysis was successfully performed on 252 of the 280 primary tumours using the SNaPshot method. Two-tailed statistical analyses were done using the χ², Fisher exact tests, and log rank tests. Cox proportional hazard ratios were estimated to obtain risks of recurrence, progression, and death, and to find independent prognostic factors in a multivariate model.

Results and limitations

FGFR3 mutations occurred with the same frequency in bladder and upper tract tumours. Mutations were associated with low-stage tumours and a milder disease course in bladder, ureter, and renal pelvis tumours. Strikingly, our data suggest that these mutations indicate a better survival in patients with invasive tumours from the bladder and upper urinary tract.

Conclusions

FGFR3 mutation status might be used to select patients with invasive UCC who have a lower risk of death.     

Potential role of photodynamic techniques combined with new generation flexible ureterorenoscopes and molecular markers for the management of urothelial carcinoma of the upper urinary tract

Study Type – Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? Sporadic clear cell Renal Cell Carcinoma (ccRCC) is dominated by mutations of the VHL gene located on chromosome 3p in up to 90% of cases. This gene plays a critical role in hypoxia response, including stimulation of neoangiogenesis. Since 2006, anti‐angiogenic therapies targeting this pathway are used in metastatic patients with objective response rate as high as 45%. However, these treatments don't target directly the tumour cell, allowing the potential for disease progression despite treatment. Large scale analysis recently showed that substantial genetic heterogeneity exists in ccRCC. Associated alterations include genes implicated in methylation regulation in 15% of cases, underlying the importance of epigenetic modifications, and truncating mutations in chromatin remodeling complex PRMB1 in 41% of cases. Systematic screening of these tumours is a way to fully determine the somatic genetic architecture of RCC in order to improve tumour classification, to develop prognostic and predictive markers and to target new molecular pathways involved in carcinogenesis.

OBJECTIVES

• ? To discuss how the development of new generation flexible ureterorenoscopes in combination with photodynamic diagnosis (PDD) improves the assessment of urothelial cell carcinoma of the upper urinary tract (UUT‐UCC).
• ? Ultimately, this may allow accurate tumour classification and the ability to select which patients would benefit from conservative treatment as opposed to radical surgery.

MATERIALS AND METHODS

• ? We conducted an exhaustive Pubmed literature search using a combination of keywords including: ureterorenoscopy, UUT‐UCC diagnosis, PDD, narrow band imaging, conservative treatment UUT‐UCC and molecular urinalysis.
• ? We then selected salient high calibre articles relevant to our objective.

RESULTS

• ? We give specific consideration to anatomical aspects of UUT‐UCC investigation, PDD in UCC, aminolevulinic acid and its derivatives, autofluorescence, narrow band imaging, molecular marker analysis and the recent advances in ureterorenoscopic technology.
• ? The traditional pitfalls of UUT‐UCC diagnosis, namely poor visualisation and difficulty in obtaining representative histological samples, are being circumvented by the introduction of modern digital flexible ureteroscopes that can be combined with PDD and molecular analysis to improve tumour classification, deferring to conservative treatment accordingly.

CONCLUSION

• ? The accuracy of the diagnostic work‐up of UUT‐UCC is improving due to advances in technology, pharmaceutical agents and incorporation of molecular markers, all factors allowing us to characterise tumours of the UUT more definitively.

     

A Functional Genetic Screen Identifies the Phosphoinositide 3-kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma

Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes.     

Evaluation of an orthotopic rat bladder urothelial cell carcinoma model by cystoscopy

OBJECTIVES

To enable preclinical testing of intravesical therapies against non‐muscle‐invasive bladder cancer (NMIBC) in an orthotopic rat bladder tumour model, augmented by the use of serial cystoscopy for in vivo tumour assessment and follow‐up.

MATERIALS AND METHODS

Fischer F344 rats had a 16‐G transurethral cannula placed. The bladder mucosa was conditioned with an acid rinse, followed by a 1‐h instillation of 1.5 × 10⁶ AY‐27 rat bladder urothelial cell carcinoma (UCC) cells (day 0). Cystoscopy (1 mm) was done on day 0 (control) and at 3, 4, 5, 6, 7, 10, 13 and 17 days. At the scheduled times the rats were killed after cystectomy (four at each time) for histopathological examination of the bladder.

RESULTS

Overall, tumour establishment was >80%, with predominantly carcinoma in situ preceding or concomitant with invasive tumour growth. All tumours were formed at 3–5 days, and remained non‐muscle‐invasive up to 5 days. From 6 days, tumours progressed to muscle‐invasive disease in 40% of the rats. Visibility at cystoscopy was excellent and tumours were apparent in >90% of rats from 5 days on, with a specificity and sensitivity of >90%. Cystoscopy could not distinguish NMIBC from muscle‐invasive disease.

CONCLUSIONS

This is a reliable model of orthotopic rat bladder UCC, with early high‐grade NMIBC growth, immediately followed by muscle‐invasive growth, i.e. the recommended time to start intravesical therapy would be 5 days after tumour cell inoculation. Tumour growth can easily be monitored by cystoscopy, but cannot be used to distinguish NMIBC from muscle‐invasive bladder cancer.     

The role of SMAD4 in early‐onset colorectal cancer

Objective Chromosomal loss within the region of 18q and loss of SMAD4 expression have been reported to be frequent somatic events during colorectal cancer tumour progression; however, their associations with age at onset have not been widely studied. Method We analysed 109 tumours from a population‐based case‐family study based on colorectal cancers diagnosed before the age of 45 years. These patients with early‐onset colorectal cancer had been previously screened for germ‐line mismatch repair gene mutations, microsatellite instability (that included the mononucleotide repeat in TGFβRII) and somatic k‐ras mutations. We measured SMAD4 protein expression using immunohistochemistry and SMAD4 copy number using quantitative real‐time PCR. Results Loss of SMAD4 protein expression was observed in 27/109 (25%) of cancers tested and was more commonly observed in rectal tumours (15/41, 36%) when compared with tumours arising in the colon (11/66, 17%) (P = 0.04). There was no association between SMAD4 protein expression and TGFβR11 mutation status, SMAD4 copy number, family history, MSI status, tumour stage or grade. Conclusion Loss of SMAD4 expression is a common feature of early‐onset colorectal tumours as it is in colorectal cancers diagnosed in other age‐groups. Taken together, the molecular pathways (genetic and epigenetic) now known to be involved in early‐onset colorectal cancer only explain a small proportion of the disease and require further exploration.     

Oncogenic role of fibroblast growth factor receptor 3 in tumorigenesis of urinary bladder cancer

Bladder cancer is the second most common genitourinary tumor and constitutes a very heterogeneous disease. Molecular and pathologic studies suggest that low-grade noninvasive and high-grade invasive urothelial cell carcinoma (UCC) arise via distinct pathways. Low-grade noninvasive UCC represent the majority of tumors at presentation. A high proportion of patients with low-grade UCC develop recurrences but usually with no progression to invasive disease. At presentation, a majority of the bladder tumors (70%–80%) are low-grade noninvasive (pTa). Several genetic changes may occur in bladder cancer, but activating mutations in the fibroblast growth factor receptor 3 (FGFR3) genes are the most common and most specific genetic abnormality in bladder cancer. Interestingly, these mutations are associated with bladder tumors of low stage and grade, which makes the FGFR3 mutation the first marker that can be used for diagnosis of noninvasive bladder tumors. Since the first report of FGFR3 involvement in bladder tumors, numerous studies have been conducted to understand its function and thereby confirm the oncogenic role of this receptor particularly in noninvasive groups. Efforts are on to exploit this receptor as a therapeutic target, which holds much promise in the treatment of bladder cancer, particularly low-grade noninvasive tumors. Further studies need to explore the potential use of FGFR3 mutations in bladder cancer diagnosis, prognosis, and in surveillance of patients with bladder cancer. This review focuses on the role of FGFR3 in bladder tumors in the backdrop of various studies published.     

Pronostic factors in recurrence and progression of superficial bladder cancer. Risk groups (part I)

IntroductionWe have carried out a retrospective study on a series of superficial bladder tumours, analyzing the clinical- pathological factors that can determine the subsequent evolution of the tumour as for recurrence and progression.Material and MethodsThey were revised on the whole 473, of which finally 419 superficial bladder tumours were useful for the study (223 primary tumours and 196 recurrent). Studies are carried out univariate and multivariate on 24 variables of each tumour referred to the characteristics and to the evolution of the tumour.ResultsWe find significant differences in the free time to recurrence, diminishing it in the tumours that recurred in less than 12 months, in multiple tumours (3 or more tumours) and in bladder dome tumours. Also statistically significant differences existed when were studied two homogeneous groups of surgeons, while the treatment with bladder instillations increased it. The time to progression, diminishes in: Tumours that had recurred prematurely (in 6 months), tumours over 3 cm, high grade tumours and when two groups of surgeons were studied, we also find that the maintenance therapy with BCG (bacillus Calmette-Guerin) showed a greater time to progression versus induction therapy.DiscussionThe independent factors to explain smaller free time till superficial recurrence were: recurrence in the 1º year, multiplicity, surgical technique, not employment of bladder washes, treatment with low dose of BCG and use of intravesical therapy with induction therapy versus maintenance. About the progression, we objectify that the factors with greater influence in the progression were, recurrence in the first 6 months, grade (grade 2 and grade 3 + Tis) and treatment with maintenance therapy versus induction.     

Large-scale real-time reverse transcription-PCR approach of angiogenic pathways in human transitional cell carcinoma of the bladder: identification of VEGFA as a major independent prognostic marker

Background

Actors of the angiogenesis pathways are targets for the new promising targeted therapies already used in several malignancies. In bladder cancer, antiangiogenic molecules could also add to already existing treatment options.

Objective

To evaluate the involvement of angiogenesis pathways in bladder carcinogenesis and identify new molecular markers having a clinical implication.

Design, setting, and participants

Expression levels of 40 genes involved in angiogenesis were assessed by quantitative real time RT-PCR in 157 urothelial tumour bladder samples obtained from patients who underwent transurethral bladder resection or radical cystectomy between 2001 and 2005. Pathologic tumour staging showed: 73 non-muscle-invasive bladder tumours (30 low-grade pTa, 14 high-grade pTa, and 29 high-grade pT1), and 84 muscle-invasive tumours (≥ pT2), all of high grade. RT-PCR results were associated with a survival analysis.

Results and limitations

VEGFA, MET, CXCR4, and IL8 were significantly overexpressed in tumour samples as compared to normal bladder tissue. VEGFA overexpressions were found in 89% of non-muscle-invasive and 66% of muscle-invasive tumour samples. In univariate analysis, for invasive tumours, VEGFA overexpression was associated with a poorer outcome in both overall and disease-free survival (p = 0.011 and 0.026 respectively) at a 13-mo median follow-up. Multivariate analysis retained T stage, N status, and VEGFA overexpression as independent prognostic factors in both overall and disease-free survival (p = 0.02 and p = 0.04, respectively, for VEGFA).

Conclusions

This study shows that, in bladder cancer, VEGFA status could be used as a prognostic factor at the individual level. VEGFA overexpression could guide a rationalized use of the costly antiangiogenic therapies which could therefore become part of the treatment options in bladder cancer.     

A comparison of the performance of microsatellite and methylation urine analysis for predicting the recurrence of urothelial cell carcinoma, and definition of a set of markers by Bayesian network analysis

OBJECTIVE

To compare the potential of two diagnostic methods for detecting recurrence of urothelial cell carcinoma (UCC) of the bladder, by (i) detecting alterations in microsatellite DNA markers and loss of heterozygosity (LOH), and (ii) detecting aberrant gene hypermethylation, as UCC has a high recurrence rate in the urinary tract and the disease can invade muscle if new tumours are overlooked.

PATIENTS AND METHODS

Over 1 year, urine samples were retrieved from 40 patients already diagnosed with bladder UCC (30 pTa, two pTis, eight pT1). Samples were collected 6 months after bladder tumour resection, during the follow‐up schedule. We used samples to analyse nine microsatellite markers and the methylation status of 11 gene promoters. Receiver operating characteristic curves were generated and Bayesian statistics used to create an interaction network between recurrence and the biomarkers.

RESULTS

During the study, 15 of the 40 patients (38%) had a tumour recurrence and 14 were identified by cystoscopy (reference method). Overall, microsatellite markers (area under curve, AUC 0.819, 95% confidence interval, CI, 0.677–0.961) had better performance characteristics than promoter hypermethylation (AUC 0.448, 0.259–0.637) for detecting recurrence. A marker panel of IFNA, MBP, ACTBP2, D9S162 and of RASSF1A, and WIF1 generated a higher diagnostic accuracy of 86% (AUC 0.92, 0.772–0.981).

CONCLUSION

Microsatellite markers have better performance characteristics than promoter hypermethylation for detecting UCC recurrence. These data support the further development of a combination of only six markers from both methods in urinary DNA. Once validated, it could be used routinely during the follow‐up for the early detection and surveillance of UCC from the lower and upper urinary tract.     

Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder

What's known on the subject? and What does the study add? Steroid hormone receptor signals have been implicated in bladder tumourigenesis and tumour progression. The expression of androgen and/or oestrogen receptors has been assessed in bladder cancer, leading to conflicting data of expression levels and their relationship to histopathological characteristics of the tumours. We simultaneously analyze three receptors in non‐neoplastic bladder tissues as well as in primary and metastatic bladder tumour specimens. Our data demonstrate that the expression status correlates with tumour grades/stages and patients’ outcomes.

OBJECTIVE

• ? To assess the expression of the androgen receptor (AR) and oestrogen receptors (ERs) in bladder tumours because recent studies have shown conflicting results and the prognostic significance of their expression remains unclear.

PATIENTS AND METHODS

• ? We investigated the expression of AR, ERα and ERβ in 188 bladder tumour specimens, as well as matched 141 non‐neoplastic bladder and 14 lymph node metastasis tissues, by immunohistochemistry.
• ? We then evaluated the relationships between their expression and the clinicopathological features available for the present patient cohort.

RESULTS

• ? AR/ERα/ERβ was positive in 80%/50%/89% of benign urothelium, 50%/67%/41% of benign stroma, 42%/27%/49% of primary tumours and 71%/64%/71% of metastatic tumours.
• ? Significantly lower expression of AR/ERα was found in high‐grade tumours (36%/23%) and tumours invading muscularis propria (33%/19%) compared to low‐grade tumours (55%; P= 0.0232/38%; P= 0.0483) and tumours not invading muscularis propria (51%; P= 0.0181/35%; P= 0.0139), respectively.
• ? Significantly higher expression of ERβ was found in high‐grade tumours (58%) and tumours invading muscularis propria (67%) compared to low‐grade tumours (29%; P= 0.0002) and tumours not invading muscularis propria (34%; P < 0.0001), respectively.
• ? Kaplan–Meier and log‐rank tests further showed that positivity of ERβ (but not AR or ERα) was associated with the recurrence of low‐grade tumours (P= 0.0072); the progression of low‐grade tumours (P= 0.0005), high‐grade tumours not invading muscularis propria (P= 0.0020) and tumours invading muscularis propria (P= 0.0010); or disease‐specific mortality in patients with tumours invading muscularis propria (P= 0.0073).

CONCLUSIONS

• ? Compared to benign bladders, a significant decrease in the expression of AR, ERα or ERβ in bladder cancer was seen.
• ? Loss of AR or ERα was strongly associated with higher grade/more invasive tumours, whereas ERβ expression was increased in high‐grade/invasive tumours and predicted a worse prognosis.

     

Functional genetic variant of WW domain containing oxidoreductase gene associated with urothelial cell carcinoma clinicopathologic characteristics and long-term survival

ObjectivesIn Taiwan, urothelial cell carcinoma (UCC) is a common malignancy of urinary tract that is associated with genetic and environmental carcinogens. WW domain-containing oxidoreductase (WWOX) has been identified as a tumor suppressor gene that associated with several cancers development and progression. The study aimed to explore the impact of WWOX gene polymorphisms on the clinicopathological status and prognosis of patients with UCC.Materials and methodsA total of 1,293 participants, including 431 patients with UCC and 862 healthy controls, were recruited for this study. Five polymorphisms of the WWOX gene were examined by a real-time PCR assay.ResultsWe found that individuals carrying TT polymorphism at rs11545028 and at least 1 G allele at rs3764340 associated with more susceptible to UCC. At least 1 A allele at rs12918952 associated with more advance disease and high grade tumor. Patients with T allele at rs11545028 associated with worse relapse free survival in all patients and worse disease specific survival (DSS) in male. Patients with A allele at rs12918952 associated with worse DSS in all patients and worse relapse free survival, DSS and overall survival in male.ConclusionsThis is the first reported correlation between WWOX polymorphisms and UCC risk and clinicopathologic feature. Genetic variants of WWOX contribute to the pathologic staging, grading, and prognosis. The findings regarding these biomarkers provided a potential prediction of UCC progression.     

Conservative treatment of upper urinary tract tumors

The histological appearance and the clinical behaviour of upper urinary tract urothelial tumours are almost identical to those of the bladder. Superficial papillary tumours rarely progress and turn to invasive disease despite a high frequency of recurrence. Technical developments in the endourology field have allowed full endoscopic access to upper tract tumours. Endoscopic resection or ablation of the tumour can be undertaken safely and effectively through ureteroscopy or percutaneous nephroscopy with low risk of extra-renal tumour seeding. For superficial (Ta, T1), low grade (I, II) tumours, a conservative approach can be selected without compromising survival and prognosis. For muscle invasive > T2 or high grade (III) tumours, nephroureterectomy remains the treatment of choice. Intracavitary BCG used after percutaneous resection reduces the risk of recurrence of upper tract urothelial tumours regardless of the grade. Finally, the world literature and our personal experience have shown that the tumour grade and stage are the two independent factors that affect survival of patients with upper urinary tract tumours.     

Prognostic variables to predict cancer-related death in incidental renal tumours

OBJECTIVE

To identify, in a large multicentre series of incidental renal tumours, the key factors that could predict cancer‐related deaths, as such tumours have a better outcome than symptomatic tumours and selected patients are increasingly being included in watchful‐waiting protocols.

PATIENTS AND METHODS

Data from 3912 patients were extracted from three international kidney‐cancer databases. Age, gender, Eastern Cooperative Oncology Group (ECOG) performance status (PS), Tumour‐Node‐Metastasis (TNM) stage, tumour size, Fuhrman grade, and final pathology were recorded. Benign tumours and malignant lesions with incomplete information were excluded from final analysis.

RESULTS

The mean (sd ) age of the patients was 60.6 (12.2) years and the mean tumour size 5.5 (3.5) cm. Most tumours were malignant (90.2%) and of low stage (T1‐T2, 71.7%) and low grade (G1‐G2, 72.4%). There were nodal and distant metastases in 5.7% and 13% of the patients. In all, 525 (14.4%) patients died from cancer; in this group, tumours were >4 cm in 88.2% and had nodal or distant metastases in 20.2% and 49.3%, respectively. Multivariable analysis showed that tumour size >4 cm, ECOG PS ≥1, TNM stage and Fuhrman grade were independent predictors of cancer‐related death.

CONCLUSION

A significant proportion of incidental renal tumours can lead to the death of the patient. Standard prognostic variables for renal cell carcinoma appear to remain valid for this subset of patients. A watchful‐waiting strategy should not be recommended if the tumour diameter is >4 cm, if biopsy confirms high‐grade tumours, or if there is an impaired ECOG PS, or computed tomography findings suggest the presence of advanced T stage.     

Impact of different grades of microscopic hematuria on the performance of urine-based markers for the detection of urothelial carcinoma

ObjectiveTo evaluate the performance of urine cytology (CYT), the UroVysion test [(fluorescence-in-situ-hybridization (FISH)], the uCyt+-test, and the nuclear matrix protein 22 ELISA (NMP22) at different grades of microscopic hematuria (HU) in a cohort of 2,365 patients suspicious for urothelial cell carcinoma (UCC).Patients and methodsA cohort of 2,365 consecutive patients suspected to have UCC underwent testing of at least 1 of the 4 noninvasive urine markers followed by cystoscopy, upper urinary tract imaging and, in case of suspicious findings, transurethral biopsy and/or resection of suspicious lesions. The grade of microscopic HU was determined by dipstick evaluation and urine microscopy and subdivided into 4 grades. The test results were compared with the HU status by contingency analysis and Cochran-Armitage test for trend separated for patients without evidence of UCC and with histologically proven UCC.ResultsIn case of grade 0, I, II, and III HU, rates of false positive CYT were 13.0, 17.4, 16.3, and 19.5% (P = 0.02), false negative CYT distributed 37.9, 18.5, 20.0, and 15.5% (P = 0.0003). FISH was false positive in 16.7, 19.8, 19.8, and 23.3% (P = 0.051) and false negative in 42.7, 27.5, 25.9, and 25.0% (P = 0.1). The uCyt+ was false positive in 12.5, 16.9, 24.0 and 35.1% (P < 0.0001), and false negative in 57.1, 26.4, 31.5, and 12.7% (P = 0.0003). NMP22 was false positive in 35.3, 55.3, 75.2, and 79.7% (P < 0.0001) and false negative in 50.0, 36.2, 22.6, and 8.2% (P < 0.0001).ConclusionThe extent of microscopic HU significantly influences the performance of noninvasive urine markers for UC. False positive rates of CYT, uCyt+, and NMP22 significantly increase with the degree of HU whereas false negative results of CYT, uCyt+, and NMP22 are less frequent in patients with high grade microscopic HU. These results underline the relevance of the grade of HU for the appropriate interpretation of urine tests.     

Role of temozolomide in spinal cord low grade astrocytomas: results in two paediatric patients

Summary Background. The optimal treatment of low grade intramedullary spinal cord tumours remains controversial. In many cases the tumours continue to progress even after surgery and radiation. Effective chemotherapy may be an important therapeutic adjunct in this setting. Temozolomide is widely used for brain gliomas, yet its role in the management of spinal cord tumours has not been reported. Procedure. Two paediatric patients with low grade spinal cord astrocytomas were diagnosed to have progression of the tumour in spite of surgery and radiotherapy. They received temozolomide, 200 mg/m² daily for five days every four weeks for 10 cycles, and were followed serially. Results. Stabilization of the spinal tumour in both patients was observed at 18 months of follow-up. One of the patients developed haematological toxicity requiring platelet transfusion and dose reduction. Conclusion. Based on our findings in two paediatric patients, temozolomide may be a useful agent in the management of progressive recurrent low grade spinal cord astrocytomas.     

Ureteral tumours showing a worse prognosis than renal pelvis tumours may be attributed to ureteral tumours more likely to have hydronephrosis and less likely to have haematuria

Purpose

To demonstrate the relationships among tumour location, hydronephrosis, and tumour stage in patients with Upper Urinary Tract Urothelial Carcinoma (UUT-UC). Moreover, we want to determine whether primary tumour location is an independent predictor of prognosis in those patients.

Methods

Retrospective analysis of 251 UUT-UC patients from our centre treated with radical nephroureterectomy between 2000 and 2010. Patients who had previous radical cystectomy, preoperative chemotherapy, previous contralateral UUT-UC, multifocal tumours, or metastatic disease at presentation were excluded. Overall, 217 patients were then available for evaluation. The relationships among tumour location, hydronephrosis, and tumour stage were analysed. Tumour location was categorized as renal pelvis or ureter. Progression-free survival (PFS) and cancer-specific survival (CSS) probabilities were estimated using Kaplan–Meier and Cox regression analyses.

Results

Tumour location was renal pelvis in 146 cases (67 %), ureter in 71 cases (33 %). Median follow-up was 52 months. Compared with renal pelvic tumours, ureteral tumours were more likely to have hydronephrosis and to be associated with advanced stages (p < 0.001), but less likely to have haematuria. The 5-year CSS estimate was 79.3 % for renal pelvic tumours and 64.7 % for ureteral tumours (p = 0.03). The 5-year PFS probability was 68.7 % for renal pelvic tumours and 54.2 % for ureteral tumours (p = 0.02). On univariable and multivariable analysis, tumour location was an independent prognostic factor for CSS (p < 0.05).

Conclusions

Ureteral tumours were associated with a worse prognosis than renal pelvis tumours. The possible hypothesis may be due partially to that ureteral tumours are more likely to have hydronephrosis and less likely to have haematuria.     

Contrast-enhanced ultrasound of hepatocellular carcinoma: correlation between enhancement pattern and cellular differentiation on histopathlogy

The aim of this study was to evaluate and correlate the enhancement pattern of hepatocellular carcinoma (HCC) on contrast-enhanced ultrasound (CEUS) and tumour cellular differentiation on histopathology. Patients underwent hepatic CEUS, performed with SonoVue and contrast pulse sequencing. The correlation between enhancement time and enhancement level of the lesions in different vascular phases and tumour cellular differentiation was determined. The tumours were graded according to the Edmondson grading system. Then, diagnosis was obtained by histopathological examination following surgery or percutaneous ultrasound-guided biopsy. 189 patients with HCC were examined with CEUS and histopathological examination between 2003 and 2009: 159 had a solitary lesion (85?%), 24 had 2 lesions (12?%) and 6 had multiple lesions (3?%). The final histological grading of the tumours was as follows: 22, 114, 49, 4 grade I?CIV, respectively. Significant differences were shown between the time that HCC become hypoenhancing or remained echogenic in late phase and tumour cellular differentiation (p?=?0.006, p?=?0.036). The timing of HCC becoming hypoenhancing was correlated with tumour cellular differentiation, with better differentiated HCCs washing out more slowly than poorly differentiated ones (p?=?0.164, p?=?0.113; p?=?0.186, p?=?0.070). The enhancement pattern of HCC by CEUS correlates with the cellular differentiation. In late phases, hyperechoic lesions are likely to be better differentiated, whereas hypoechoic lesion is more likely to be poorly differentiated.     

Gene expression analysis for the prediction of recurrence in patients with primary Ta urothelial cell carcinoma

OBJECTIVES: The individual recurrence-free period after primary surgery of patients with Ta urothelial cell carcinoma (UCC) cannot be predicted accurately. This study aims at discriminating between patients with primary Ta UCC and long or short recurrence-free periods. METHODS: We investigated mRNA expression of 23 genes in 44 primary Ta tumours (23 and 21 tumours were from patients with long [>or=4 yr] or short [相似文献   

Outcomes of 101 Consecutive Surgical Resections of Gastroenteropancreatic Neuroendocrine Tumours (GEPNETs) at Tata Memorial Hospital: a Referral Bias for Nonfunctional Duodenopancreatic Tumours and the Need for Greater Awareness of GEPNETs as a Distinct Entity

Data from India regarding the disease spectrum and surgical results of neuroendocrine tumours (GEPNETs) are sparse. Tempered surgical radicality in a high-volume oncology centre, conforming to existing guidelines, may further our understanding of tumour characteristics and behavioural patterns of nonfunctional GEPNETs. Surgical outcomes of patients with histopathologically confirmed GEPNETs from January 2003 to December 2013 were analyzed from a prospectively maintained database. Tumour grade, organ of primary tumour, perioperative factors, quality/radicality of resection and presence of metastatic disease were correlated with perioperative outcomes, overall survival and disease-free survival. Ninety of the 101 operated patients had nonfunctional tumours. These comprised radical resections (n?=?69), organ-preserving procedures (n?=?16) and inoperable tumours (n?=?5). The primary tumour sites were pancreatic in 48 patients and gastroenteric in 42 patients. The overall perioperative morbidity and mortality rates were 30 and 3 %, respectively. Fifteen patients harboured metastatic disease at presentation. At a median follow-up of 22 months, 18 patients had residual disease, 7 developed recurrences and 10 patients died. The estimated actuarial 5-year overall survival was 81.6 %, and disease-free survival was 67.2 %. Tumour grade and organ of origin (pancreatic vs. gastroenteric) did not influence long-term survival (p?=?0.315 and p?=?0.624, respectively), but presence of metastatic disease at presentation significantly affected long-term survival (p?=?0.009). Nonfunctional pancreatic/duodenal neuroendocrine tumours (NETs) accounted for 76 % of surgical resections at our centre with the minority being other resections. In selected patients with nonfunctional NETs, organ-preserving surgery may provide equivalent long-term survival with decreased operative morbidity. Although tumour grade is considered to be an important prognostic factor, the presence of metastatic disease at presentation also determines long-term survival. The referral bias suggests the need for greater awareness given the favourable long-term outcomes of these tumours. There is a need to correct this referral bias by increasing the awareness of GEPNETs in India.     

Underestimation of Gleason score at prostate biopsy reflects sampling error in lower volume tumours

Study Type – Diagnostic (case series) Level of Evidence 4 What's known on the subject? and What does the study add? The Gleason score of prostate cancer is frequently underestimated at the time of diagnostic biopsy, although the contribution of sampling error to its incidence is unknown. We show that under‐graded tumours are significantly smaller that tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error.

OBJECTIVE

• ? To determine the influence of tumour and prostate gland volumes on the underestimation of prostate cancer Gleason score in diagnostic core biopsies.

PATIENTS AND METHODS

• ? Patients undergoing radical prostatectomy with matched diagnostic biopsies were identified from a prospectively recorded database.
• ? Tumour volumes were measured in serial whole‐mount sections with image analysis software as part of routine histological assessment.
• ? Differences in various metrics of tumour and prostate volume between upgraded tumours and tumours concordant for the lower or higher grade were analysed.

RESULTS

• ? In all, 684 consecutive patients with Gleason score 6 or 7 prostate cancer on diagnostic biopsy were identified.
• ? Of 298 patients diagnosed with Gleason 6 tumour on biopsy, 201 (67.4%) were upgraded to Gleason 7 or higher on final pathology. Similarly, of 262 patients diagnosed with Gleason 3 + 4 = 7 prostate cancer on initial biopsy, 60 (22.9%) were upgraded to Gleason score 4 + 3 = 7 or higher.
• ? Tumours upgraded from Gleason 6 to 7 had a significantly lower index tumour volume (1.73 vs 2 mL, P= 0.029), higher calculated prostate volume (41.6 vs 39 mL, P= 0.017) and lower relative percentage of tumour to benign glandular tissue (4.3% vs 5.9%, P= 0.001) than tumours concordant for the higher grade.
• ? Similarly, tumours that were Gleason score 3 + 4 on biopsy and upgraded on final pathology to 4 + 3 were significantly smaller as measured by both total tumour volume (2.3 vs 3.3 mL, P= 0.005) and index tumour volume (2.2 vs 3, P= 0.027) and occupied a smaller percentage of the gland volume (6.3% vs 8.9%, P= 0.017) compared with tumours concordant for the higher grade.
• ? On multivariate analysis, lower prostate weight (hazard ratio 0.97, 95% confidence interval 0.96–0.99, P < 0.001) and larger total tumour volume (hazard ratio 1.87, 95% confidence interval 1.4–2.6, P < 0.001) independently predicted an upgrade in Gleason score from 6 to 7. In tumours upgraded from biopsy Gleason 3 + 4, only higher index tumour volume (hazard ratio 3.1, 95% confidence interval 1.01–9.3, P= 0.048) was a significant predictor of upgrading on multivariate analysis.

CONCLUSIONS

• ? Under‐graded tumours are significantly smaller than tumours concordant for the higher grade, indicating that incomplete tumour sampling plays a significant role in Gleason score assignment error.
• ? Surrogate measures of tumour volume may predict those at greatest risk of Gleason score upgrade.