Combining two grading systems: the clinical validity and inter-observer variability of the 1973 and 2004 WHO bladder cancer classification systems assessed in a UK cohort with 15 years of prospective follow-up.

PURPOSE: Paucity of reliable long-term data on the prognostic implications of the 2004 WHO bladder cancer classification system necessitates utilisation of both this and the 1973 grading systems. This study evaluated, in noninvasive (pTa) bladder tumours, the prognostic value of the 2004 system independently and in combination with the 1973 system while establishing concordance between tertiary centre uropathologists. METHODS: We used a cohort of non-muscle invasive bladder cancer (NMIBC) patients diagnosed between 1991 and 93 where tumour features were gathered prospectively with detailed cystoscopic follow-up data recorded over 15 years. Initial grading was by one senior expert uropathologist (UP1) using the 1973 WHO classification alone. Subsequently, two other expert uropathologists (UP2 and UP3), blinded to the previous grading, re-evaluated the pathology slides and graded the tumours using both the 1973 and 2004 systems. Association between grade and recurrence/progression was analysed and the Cohen Kappa test assessed concordance between pathologists. RESULTS: Of 370 new NMIBC, 229 were staged noninvasive (pTa). Recurrence rates were 46.2% and 50.0% for LGPUC (low-grade papillary urothelial carcinoma) and HGPUC (high-grade papillary urothelial carcinoma), respectively, while progression was seen in 3.9% and 10.0% of LGPUC and HGPUC, respectively. Concordance between uropathologists UP2 and UP3 for the 2004 and 1973 systems was good (Kappa = 0.69) and fair (Kappa = 0.25), respectively. CONCLUSIONS: With good inter-observer concordance, the 2004 WHO classification system of noninvasive bladder tumours appears to accurately predict recurrence and progression risks. The combination of both grading systems to low-grade tumours allows further refinement of the natural history.

Good quality white-light transurethral resection of bladder tumours (GQ-WLTURBT) with experienced surgeons performing complete resections and obtaining detrusor muscle reduces early recurrence in new non-muscle-invasive bladder cancer: validation across time and place and recommendation for benchmarking.

UNLABELLED: Study Type - Therapy (cohort) Level of Evidence 2b What's known on the subject? and What does the study add? Apart from bladder tumour multiplicity, size, stage, grade and presence of cis, early recurrence following white light TURBT for new bladder tumours is also determined by surgeon experience, completeness of resection and presence or absence of detrusor muscle in the specimen. This study aims to validate surgeon experience and detrusor muscle as independent predictors of early recurrence following apparently complete white light TURBT in new bladder tumours. OBJECTIVE: To validate in patients undergoing first transurethral resection of bladder tumour (TURBT) for non-muscle-invasive bladder cancer (NMIBC), the presence/absence of detrusor muscle (DM) in the specimen and surgeon experience as independent predictors of the quality of TURBT. PATIENTS AND METHODS: Patients with new NMIBC, who had undergone complete first resections were recruited from a prospectively maintained cohort from the 1980s at the Western General Hospital, Edinburgh, UK and a contemporary cohort from the Aberdeen Royal Infirmary, UK. Tumour size, multiplicity, surgeon category, presence or absence of DM in the specimen, grade, stage, findings at first check cystoscopy and early re-TURBT were evaluated. Surgeons were stratified into a senior group (consultant and trainees in year five or six) and a junior group (trainees below year five). Early recurrence, or recurrence rate at the first follow up cystoscopy (RRFFC), was used to measure quality and was defined as finding pathologically confirmed tumour at early re-TURBT or the first check cystoscopy. RESULTS: From a total of 566 patients evaluated from both cohorts, 473 NMIBC specimens were suitable for analysis. Logistic regression multivariate analysis revealed that the absence of DM was associated with a higher RRFFC (odds ratio [OR]= 3.6, 95% CI = 1.7-7.5, P < 0.001). Senior surgeons were more likely to resect DM (OR = 4.9, 95% CI = 2.3-10.7, P < 0.001) Senior surgeons were independently associated with a lower RRFFC (OR = 5.3, 95% CI = 2.1-12.9, P < 0.001). CONCLUSIONS: Detrusor muscle status at the first, apparently complete, TURBT and surgeon's experience independently predict the quality of TURBT. • Documented complete resection by experienced surgeons with DM presence (good quality white-light TURBT) should be considered a benchmark for white-light TURBT in NMIBC.

BA08: An open-label, single-arm, non-randomised, phase 2 trial of cisplatin, methotrexate and vinblastine (CMV) for pure squamous cell cancer of the urinary tract.

BACKGROUND: Pure squamous cell carcinoma (SCC) of the urinary tract is rare in the UK and has a poor prognosis compared with transitional cell carcinoma (TCC). Cisplatin based chemotherapy has been shown to be effective in TCC. METHODS: Patients with T3-T4, pelvic relapsed, nodal or metastatic SCC of the urinary tract were recruited into an open-label, single-arm, non-randomised, phase 2 trial evaluating the activity and safety of cisplatin, methotrexate and vinblastine (CMV) chemotherapy. CMV was given as three 21-day cycles of methotrexate 30mg/m2 (day 1 & 8), vinblastine 4mg/m2 (day 1 & 8) and cisplatin 100mg/m2 (day 2). RESULTS: 38 patients were recruited. Overall response was 39% (95% CI 24%, 55%)-13% CR and 26% PR. Median OS was 7.8 months (95% CI 3.4, 12.6) with 39% 1-year survival. Toxicity was acceptable. CONCLUSION: CMV is well tolerated and active in patients with pure SCC of the urinary tract.

Progression to detrusor-muscle invasion in bladder carcinoma is associated with polysomy of chromosomes 1 and 8 in recurrent pTa/pT1 tumours.

Transitional cell carcinoma (TCC) provides a unique model of cancer recurrence and progression. Sequential tumours (n=100) from 57 patients with an index pTa or pT1 TCC were studied using fluorescence in situ hybridisation (FISH), to determine aberrations of chromosomes 1 and 8. Thirty-seven patients experienced recurrences; eleven developed muscle invasive tumours (pT2+). Polysomy of chromosomes 1 or 8 was associated with pT1 TCC (P=0.0017 and P=0.0037, respectively), but not with recurrence. Progression was associated with polysomy of chromosomes 1 (P=0.003) and 8 (P=0.011) in pTa/pT1 recurrences, but not with stage. In conclusion, patients who subsequently developed invasive TCC (pT2+) had significantly higher rates of aneusomy (90%) in their superficial cancers than those patients who did not progress (P=0.009). Investigation of sequential tumours in patients with recurrent and progressive TCC showed that polysomy of chromosomes 1 and 8 were linked to subsequent detrusor muscle invasion, but not recurrence per se.

Extra embryonic elements in testicular tumours.

Extra embryonic elements in germ cell tumours resemble the trophectoderm or yolk sac endoderm which are the extra embryonic membranes of the developing embryo. True chorionic (trophoblastic) differentiation with syncytiotrophoblast and cytotrophoblast, perhaps with a villous pattern, is rare and is associated with a very poor prognosis and with hCG production. Isolated syncytiotrophoblastic cells also produce hCG but are prognostically less sinister. Yolk sac elements occur in two thirds of non seminomatous germ cell tumours, and affect all age groups. Pure forms of yolk sac tumour (YST) occur but are not common except in infants. They are often associated with AFP production but AFP is not a specific marker for YST. Yolk sac tumours have a similar prognosis to malignant teratoma undifferentiated (MTU: embrvonal carcinoma).

A unique case of an alpha-fetoprotein-producing lung cancer with testicular metastasis.

Alpha-fetoprotein (AFP)-producing primary lung tumours are rare; we present the first case of an AFP-producing lung tumour with metastasis to testes. The patient, a 72-year-old man, presented with a history of flu-like symptoms and abdominal pain. On examination he had a hard, tender left scrotal mass. Imaging showed a 4.4-cm right lower lobe lung mass and the serum-AFP was raised (1189 ng/mL). Left orchidectomy excised a necrotic tumour. Microscopy showed complete hemorrhagic infarction and immunohistochemistry showed a lack of staining for AFP. Serum-AFP rose 3 days post-orchidectomy to 1466 ng/mL. The patient subsequently developed melaena and died. Autopsy revealed a 9 × 5-cm necrotic right lower lobe lung tumour. Immunohistochemistry showed the tumour cells reacted with a pan-cytokeratin antibody and less than 5% expressed AFP. Bilateral adrenal tumour deposits were also identified in addition to those in the bowel and spleen. The expression of AFP solely in the lung lesion and lack of expression in both testes, together with a rise in serum-AFP post-orchidectomy and the bilateral adrenal metastases, is overwhelming evidence for the reversal of the usual situation: a poorly differentiated AFP-secreting metastatic lung adenocarcinoma.

Detrusor muscle in the first, apparently complete transurethral resection of bladder tumour specimen is a surrogate marker of resection quality, predicts risk of early recurrence, and is dependent on operator experience.

BACKGROUND: An European Organisation for Research and Treatment of Cancer analysis of multicentre trials found significant interinstitutional variability in recurrence rates at first follow-up cystoscopy (RR-FFC) and attributed this to variable transurethral resection of bladder tumour (TURBT) quality. OBJECTIVE: To determine whether resection of detrusor muscle (DM) in the first, apparently complete TURBT is a surrogate marker of quality and whether the presence of DM is dependent on a surgeon's experience. DESIGN, SETTING, AND PARTICIPANTS: Over a 2-yr period, patients with new bladder tumours that were judged to have been completely resected were recruited from our prospectively maintained bladder tumour database. Strict exclusion criteria were applied. MEASUREMENTS: Prospectively recorded tumour size, tumour multiplicity, surgeon category, DM status, grade and stage of tumour, and findings at first follow-up cystoscopy (at 3 mo) and at early re-TURBT were evaluated. Surgeons were stratified into seniors (consultants and year 5 or year 6 trainees) and juniors (trainees lower than year 5). Early recurrence (for calculating RR-FFC) was defined as pathologically confirmed tumour on early re-TURBT or recurrence at the first follow-up cystoscopy. Logistic regression multivariate analyses were carried out to determine associations between variables. RESULTS AND LIMITATIONS: In a total of 356 patients, DM was present in 241 patients (67.7%). Multivariate analyses revealed that large tumours, high-grade tumours, and surgery by senior surgeons was independently associated with the presence of DM in the resected specimens. The RR-FFCs when DM was absent and present were 44.4% and 21.7%, respectively (odds ratio: 2.9; 95% confidence interval: 1.6-5.4; p=0.0002). The absence of DM and resection by less experienced surgeons independently predicted a higher RR-FFC. This association was also seen in small and low-grade tumours. The number of patients in this study appears modest, and further validation may be required. CONCLUSIONS: DM absence or presence in the first, apparently complete TURBT specimen appears to be a surrogate marker of resection quality by independently predicting the RR-FFC, which is also dependent on surgeon experience.

Pattern of recurrence changes in noninvasive bladder tumors observed during 2 decades.

PURPOSE: Previously published data on the 25-year outcome of G1Ta and G2Ta bladder tumors demonstrated that both tumors have a similarly low risk of recurrence in cases in which no tumor was detected in the first 5 years after presentation. A further 4 prospectively maintained cohorts were available for comparison between institutions or across time periods. MATERIALS AND METHODS: Review of a prospectively kept, computerized record of patients with bladder cancer allowed analysis of the long-term outcome of 4 further cohorts of bladder cancer presenting in 1978 to 1986 or 1991 to 1996. RESULTS: A total of 325 patients with G1Ta and 190 with G2Ta bladder tumors had up to 25 years of followup. The risk of recurrence in the first 5 years was identical in all cohorts from the 1980s. However, in those patients without recurrence in the initial 5 years, the subsequent risk of recurrence (in G1 and G2Ta tumors) was 3.2% in the earlier cohorts but increased 3-fold to 10.8% in the cohorts from the early 1990s (RR 3.3, 95% CI 1.2-9.5, p=0.016). CONCLUSIONS: A difference was observed in the pattern of late biopsy proven recurrence in the more contemporary cases. Increased use of prophylactic intravesical chemotherapy does not seem to be a strong factor. Changes in the ability to detect lesions and the readiness to biopsy suspicious lesions may be responsible for this difference.

Identification of loci associated with putative recurrence genes in transitional cell carcinoma of the urinary bladder.

Following an earlier study linking monosomy 9 with recurrence of transitional cell carcinomas (TCCs) of the urinary bladder, 109 primary and recurrent TCCs (from 47 patients) were examined to explore genetic alterations at chromosome 9 associated with recurrence. Patient DNA was microdissected and extracted from archival tissue sections and analysed for loss of heterozygosity (LOH) at three regions on chromosome 9 where tumour suppressor genes (TSGs) are known to reside (INK 4A, DBC1, and TSC1). Patients were categorized into two groups, non-recurrent TCC (NR, n=18) and recurrent TCC (REC, n=29). It was noted that 12% of NR tumours, compared with 54% of REC primary tumours (p=0.01), had LOH at all informative markers spanning the TSC1 region. The risk of recurrence was significantly higher in patients with deleted TSC1 than in those who retained the TSC1 region (p=0.035). Levels of LOH at DBC1 or INK 4A were not significantly different in NR tumours than in REC primary tumours and recurrence-free survival was not affected by loss of either of these genes. Loss of all informative markers spanning chromosome 9 was observed in 0% of NR tumours compared with 25% of REC primary tumours (p=0.04). The probability of recurrence was also significantly increased in patients who had LOH at all informative markers spanning chromosome 9 (p=0.016), confirming earlier fluorescence in situ hybridization results. This study provides further evidence that recurrence in bladder cancer is a distinct event, with underlying molecular causes. It also identifies the TSC1 locus as a candidate for a TSG, which drives recurrence in a proportion of TCC patients. Loss of all informative markers, including those residing in the TSC1 region, spanning chromosome 9 was also linked to recurrence.

Can p53 staining be used to identify patients with aggressive superficial bladder cancer?

Approximately 10% of patients with superficial bladder cancer (pTa/pT1) recur with life-threatening muscle-invasive disease. Identification of these patients has been a major goal of bladder cancer research. In 1994, it was suggested that p53 immunostaining could identify the cancers that would progress and it was proposed that tumours that stain for p53 should be treated aggressively with radiotherapy or cystectomy. Despite the hundreds of studies published since on the relationship between p53 and progression in superficial bladder cancer, the clinical utility of p53 immunostaining has not been resolved because of limitations concerning the numbers of patients and the length of follow-up. This study set out to overcome these limitations by using tissue from a large multicentre trial that recruited 502 patients with a median follow-up of 10 years. Each of 34 patients that had progressed with >/= pT2 disease or had distant metastases or had died from bladder cancer was compared with one or two matched controls. Sections were stained with a mouse monoclonal antibody to p53, pAb1801. In agreement with many of the earlier studies, p53 immunostaining had prognostic significance. The adjusted hazard ratio for time to progression for the pAb1801-positive versus negative group was 2.5, with 95% confidence intervals of 1.05-5.98 (p = 0.039). The other major risk factor that is associated with progression of superficial bladder cancer is pT1G3 disease. Of the 42 pT1G3 cancers, 14 (33%) progressed. The proportion of cancers with p53 staining that progressed was similar to the proportion of pT1G3 cancers that progressed, but neither the sensitivity nor the specificity of association of p53 staining with progression is sufficient to recommend cystectomy in individual patients.