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1292 UROTHELIAL CELL CARCINOMA IN PATIENTS WITH KNOWN GERMLINE MUTATIONS FOR LYNCH SYNDROME
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THE JOURNAL OF UROLOGY姞
from 1987 to 2009. Patients were stratified by tobacco history into non-smokers, light-smokers (ⱕ30 pack/years), and heavy-smokers (⬎30 pack/years). Clinicopathologic characteristics of the initial presentation and initial bladder tumor were analyzed. Variables included gender, race, BMI, initial presenting symptom, tumor grade, clinical stage, lymph-vascular invasion (LVI), clinical CIS, packs per day (PPD), years of smoking, and years since smoking cessation. One-way ANOVA was used for continuous variables, and chi squared test for categorical variables. Logistic regression was used to calculate odds ratio (OR) for muscle invasive bladder cancer (MIBC) at initial presentation. RESULTS: Of the 740 patients available for analysis, 197 (26.6%) were non-smokers, 251 (33.9%) were light smokers, and 292 (39.5%) were heavy smokers. No difference was seen for race (p⫽0.29) and BMI (p⫽0.23); however males were more likely to be heavy smokers compared to females (44.5% v. 23.6% p⫽⬍0.001). Compared to non-smokers and light smokers, the initial tumors in heavy smokers were more likely to be high grade (p⫽0.02), have a more advanced clinical stage (p⫽0.05), and to present with MIBC (p⫽0.04). No statistical difference was seen regarding LVI (p⫽0.63) and clinical CIS (p⫽0.2). Heavy smokers were also more likely to have gross hematuria as presenting symptom (p⫽0.06). When compared to non-smokers, the OR for presenting with MIBC was 1.18 (95%CI⫽0.682.1) for light smokers and 1.38 (95%CI⫽1.06-1.8) for heavy. When adjusting for gender, heavy smoking remained a risk for presenting with MIBC for males (p⫽0.02), but not for females (p⫽0.7). CONCLUSIONS: When compared to non-smokers and light smokers, patients with a ⬎30 pack/years smoking history are more likely to have higher grade tumors, more advanced clinical stage, and an increased risk of muscle invasion at initial presentation. This effect appears to be greater in male heavy smokers compared to females. Source of Funding: None
1292 UROTHELIAL CELL CARCINOMA IN PATIENTS WITH KNOWN GERMLINE MUTATIONS FOR LYNCH SYNDROME Timothy F. Donahue*, Vanessa Hui, Philip Kim, John P. Sfakianos, Brooke Sylvester, Tullika Garg, Behfar Ehdaie, Hikmat Al-Ahmadie, Rohini Rau-Murthy, Zsofia Stadler, Jose Guillem, Bernard H. Bochner, New York, NY INTRODUCTION AND OBJECTIVES: Lynch syndrome (LS) is a cancer syndrome caused by autosomal dominant inheritance of mismatch repair gene mutations (MMR). LS has traditionally been associated with an increased risk of colon cancer; however, malignancies of other organs, including urothelial cell cancers (UC), have also been implicated. The objective of this study was to assess the frequency of bladder and upper urinary tract tumors in patients with documented LS. METHODS: After IRB approval, a retrospective review of the Memorial Sloan-Kettering Cancer Center (MSKCC) Cologene and clinical genetics databases was conducted. We included all patients with a documented germline mutation for LS and a history of urothelial carcinoma of the bladder (B-UC), upper urinary tract (UUT-UC), or both. Family history obtained at the time of UC diagnosis was compared to the Amsterdam II criteria for the clinical diagnosis of LS. RESULTS: Of patients with known LS germline mutations and a LS-associated malignancy in our database, 14 had a history of B-UC, UUT-UC, or both. Average age at UC diagnosis was 52.2 yrs and 50% of subjects were male. The average age at first cancer diagnosis was 46.6 years for non-GU malignancies, an average of 5.6 yrs sooner than the diagnosis of a GU malignancy. Germline MSH2 mutations were present in 78.6%, MLH1 mutations in 7.2%, and PMS2 mutations in 14.2% of patients. Eight of 14 subjects (57%) had B-UC and for 5 subjects (35.7%) B-UC was the initial diagnosis of malignancy. Five B-UC subjects (62.5%) had MSH2 mutations, two (25%) had PMS2 mutations, and one (12.5%) had an MLH1 mutation. Four of 8 patients (50%) with bladder cancer also had UUT-UC. Ten of 14 (71.4%)
Vol. 189, No. 4S, Supplement, Monday, May 6, 2013
patients had UUT-UC and all 10 patients had germline MSH2 mutations. Complete family history was available for 10 subjects and 7 subjects met Amsterdam II clinical criteria for LS. CONCLUSIONS: In our series, 14 patients with a genetic diagnosis of LS had UC. In 35.7% of these patients, B-UC was the presenting malignancy leading to a diagnosis of LS. Nearly two-thirds of B-UCC tumors were associated with MSH2 mutations. B-UC may be more common than previously described in LS patients. Urologists should be aware of the possibility of LS in the UC population and perform screening through careful family history. Source of Funding: None
1293 A META-ANALYSIS OF BLUE LIGHT CYSTOSCOPY WITH HEXAMINOLEVULINATE IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER Leonard Gomella*, Philadelphia, PA; H. Barton Grossman, Houston, TX; Michael Droller, New York, NY; Jorg Schmidbauer, Vienna, Austria; Gregers Hermann, Copenhagen, Denmark; Octavian Dragoescu, Craiova, Romania; Eleanor Ray, London, United Kingdom; Alfred Witjes, Nijmegen, Netherlands; Alexander Karl, Munich, Germany; Arnulf Stenzl, tuebingen, Germany; Yves Fradet, Quebec, Canada; Juan Burgues, Palma de Mallorca, Spain; Dieter Jocham, Lubeck, Germany INTRODUCTION AND OBJECTIVES: To assess the available clinical data for blue light (BL) cystoscopy with hexaminolevulinate on the detection of papillary (Ta/T1) and flat (CIS) tumors, and on tumor recurrence. METHODS: A meta-analysis was conducted on raw patient data from eight prospective studies totalling 1293 patients. Studies included consecutively enrolled patients with known or suspected nonmuscle invasive bladder cancer, and used BL cystoscopy with hexaminolevulinate as an adjunct to white light (WL) cystoscopy (equipment from Karl Storz, Germany) in randomized groups or within-patient comparison. Intention-to-treat populations (n⫽790) were used for detection analysis and Per Protocol for recurrence (n⫽634). Analysis was also carried out on sub-groups of patients: initial or recurrent cancer; high, intermediate and low risk; and previous treatment. RESULTS: There were 21.3% (168/790) patients in whom at least one additional Ta/T1 tumor was detected only with BL (p⬍0.001; event rate⫽0.217 [0.193-0.247]). In initial and recurrent sub-groups, lesions were seen only with BL in 16.8% (58/346) and 24.8% (110/444) of patients, respectively (p⬍0.001). In patients who had received prior BCG or chemotherapy, lesions were seen only under BL in 25% (48/192) patients (p⬍0.001). In those patients who had at least one CIS lesion at diagnosis, CIS lesions were seen only with BL in 61/256 (23.8%) patients, while no CIS lesions were seen with white light (p⬍0.001; ER⫽0.246 [0.196-0.304]). At lesion level BL cystoscopy detected significantly more Ta tumors (13.2%; p⬍0.001, OR⫽2.136 [CI: 1.578 –2.890]), than WL cystoscopy. The benefit was particularly significant in high risk (p⫽0.007) and intermediate risk Ta patients (p⬍0.001) and in T1 patients with initial cancer (11.2%; p⫽0.003, OR⫽3.978 [CI: 1.617–9.785]). There was also a significant benefit in patients who had received prior BCG or chemotherapy (p⬍0.001). Recurrence rates measured at 9 –12 months were significantly lower overall with BL: 34.5% BL vs 45.4% WL (p⫽0.006, risk ratio⫽0.781). Risk ratios for recurrence were also lower in the sub-groups of patients with T1 or CIS (p⫽0.052, RR⫽0.696), and those with Ta (p⫽0.004, RR⫽0.804). CONCLUSIONS: This meta-analysis confirmed that BL cystoscopy with hexaminolevulinate added to WL cystoscopy significantly assists the detection of bladder tumors at both a patient and tumor level. The benefit of improved detection with BL cystoscopy led to improved clinical outcomes by reducing recurrence rates at 9 –12 months. Source of Funding: None
THE JOURNAL OF UROLOGY姞
from 1987 to 2009. Patients were stratified by tobacco history into non-smokers, light-smokers (ⱕ30 pack/years), and heavy-smokers (⬎30 pack/years). Clinicopathologic characteristics of the initial presentation and initial bladder tumor were analyzed. Variables included gender, race, BMI, initial presenting symptom, tumor grade, clinical stage, lymph-vascular invasion (LVI), clinical CIS, packs per day (PPD), years of smoking, and years since smoking cessation. One-way ANOVA was used for continuous variables, and chi squared test for categorical variables. Logistic regression was used to calculate odds ratio (OR) for muscle invasive bladder cancer (MIBC) at initial presentation. RESULTS: Of the 740 patients available for analysis, 197 (26.6%) were non-smokers, 251 (33.9%) were light smokers, and 292 (39.5%) were heavy smokers. No difference was seen for race (p⫽0.29) and BMI (p⫽0.23); however males were more likely to be heavy smokers compared to females (44.5% v. 23.6% p⫽⬍0.001). Compared to non-smokers and light smokers, the initial tumors in heavy smokers were more likely to be high grade (p⫽0.02), have a more advanced clinical stage (p⫽0.05), and to present with MIBC (p⫽0.04). No statistical difference was seen regarding LVI (p⫽0.63) and clinical CIS (p⫽0.2). Heavy smokers were also more likely to have gross hematuria as presenting symptom (p⫽0.06). When compared to non-smokers, the OR for presenting with MIBC was 1.18 (95%CI⫽0.682.1) for light smokers and 1.38 (95%CI⫽1.06-1.8) for heavy. When adjusting for gender, heavy smoking remained a risk for presenting with MIBC for males (p⫽0.02), but not for females (p⫽0.7). CONCLUSIONS: When compared to non-smokers and light smokers, patients with a ⬎30 pack/years smoking history are more likely to have higher grade tumors, more advanced clinical stage, and an increased risk of muscle invasion at initial presentation. This effect appears to be greater in male heavy smokers compared to females. Source of Funding: None
1292 UROTHELIAL CELL CARCINOMA IN PATIENTS WITH KNOWN GERMLINE MUTATIONS FOR LYNCH SYNDROME Timothy F. Donahue*, Vanessa Hui, Philip Kim, John P. Sfakianos, Brooke Sylvester, Tullika Garg, Behfar Ehdaie, Hikmat Al-Ahmadie, Rohini Rau-Murthy, Zsofia Stadler, Jose Guillem, Bernard H. Bochner, New York, NY INTRODUCTION AND OBJECTIVES: Lynch syndrome (LS) is a cancer syndrome caused by autosomal dominant inheritance of mismatch repair gene mutations (MMR). LS has traditionally been associated with an increased risk of colon cancer; however, malignancies of other organs, including urothelial cell cancers (UC), have also been implicated. The objective of this study was to assess the frequency of bladder and upper urinary tract tumors in patients with documented LS. METHODS: After IRB approval, a retrospective review of the Memorial Sloan-Kettering Cancer Center (MSKCC) Cologene and clinical genetics databases was conducted. We included all patients with a documented germline mutation for LS and a history of urothelial carcinoma of the bladder (B-UC), upper urinary tract (UUT-UC), or both. Family history obtained at the time of UC diagnosis was compared to the Amsterdam II criteria for the clinical diagnosis of LS. RESULTS: Of patients with known LS germline mutations and a LS-associated malignancy in our database, 14 had a history of B-UC, UUT-UC, or both. Average age at UC diagnosis was 52.2 yrs and 50% of subjects were male. The average age at first cancer diagnosis was 46.6 years for non-GU malignancies, an average of 5.6 yrs sooner than the diagnosis of a GU malignancy. Germline MSH2 mutations were present in 78.6%, MLH1 mutations in 7.2%, and PMS2 mutations in 14.2% of patients. Eight of 14 subjects (57%) had B-UC and for 5 subjects (35.7%) B-UC was the initial diagnosis of malignancy. Five B-UC subjects (62.5%) had MSH2 mutations, two (25%) had PMS2 mutations, and one (12.5%) had an MLH1 mutation. Four of 8 patients (50%) with bladder cancer also had UUT-UC. Ten of 14 (71.4%)
Vol. 189, No. 4S, Supplement, Monday, May 6, 2013
patients had UUT-UC and all 10 patients had germline MSH2 mutations. Complete family history was available for 10 subjects and 7 subjects met Amsterdam II clinical criteria for LS. CONCLUSIONS: In our series, 14 patients with a genetic diagnosis of LS had UC. In 35.7% of these patients, B-UC was the presenting malignancy leading to a diagnosis of LS. Nearly two-thirds of B-UCC tumors were associated with MSH2 mutations. B-UC may be more common than previously described in LS patients. Urologists should be aware of the possibility of LS in the UC population and perform screening through careful family history. Source of Funding: None
1293 A META-ANALYSIS OF BLUE LIGHT CYSTOSCOPY WITH HEXAMINOLEVULINATE IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER Leonard Gomella*, Philadelphia, PA; H. Barton Grossman, Houston, TX; Michael Droller, New York, NY; Jorg Schmidbauer, Vienna, Austria; Gregers Hermann, Copenhagen, Denmark; Octavian Dragoescu, Craiova, Romania; Eleanor Ray, London, United Kingdom; Alfred Witjes, Nijmegen, Netherlands; Alexander Karl, Munich, Germany; Arnulf Stenzl, tuebingen, Germany; Yves Fradet, Quebec, Canada; Juan Burgues, Palma de Mallorca, Spain; Dieter Jocham, Lubeck, Germany INTRODUCTION AND OBJECTIVES: To assess the available clinical data for blue light (BL) cystoscopy with hexaminolevulinate on the detection of papillary (Ta/T1) and flat (CIS) tumors, and on tumor recurrence. METHODS: A meta-analysis was conducted on raw patient data from eight prospective studies totalling 1293 patients. Studies included consecutively enrolled patients with known or suspected nonmuscle invasive bladder cancer, and used BL cystoscopy with hexaminolevulinate as an adjunct to white light (WL) cystoscopy (equipment from Karl Storz, Germany) in randomized groups or within-patient comparison. Intention-to-treat populations (n⫽790) were used for detection analysis and Per Protocol for recurrence (n⫽634). Analysis was also carried out on sub-groups of patients: initial or recurrent cancer; high, intermediate and low risk; and previous treatment. RESULTS: There were 21.3% (168/790) patients in whom at least one additional Ta/T1 tumor was detected only with BL (p⬍0.001; event rate⫽0.217 [0.193-0.247]). In initial and recurrent sub-groups, lesions were seen only with BL in 16.8% (58/346) and 24.8% (110/444) of patients, respectively (p⬍0.001). In patients who had received prior BCG or chemotherapy, lesions were seen only under BL in 25% (48/192) patients (p⬍0.001). In those patients who had at least one CIS lesion at diagnosis, CIS lesions were seen only with BL in 61/256 (23.8%) patients, while no CIS lesions were seen with white light (p⬍0.001; ER⫽0.246 [0.196-0.304]). At lesion level BL cystoscopy detected significantly more Ta tumors (13.2%; p⬍0.001, OR⫽2.136 [CI: 1.578 –2.890]), than WL cystoscopy. The benefit was particularly significant in high risk (p⫽0.007) and intermediate risk Ta patients (p⬍0.001) and in T1 patients with initial cancer (11.2%; p⫽0.003, OR⫽3.978 [CI: 1.617–9.785]). There was also a significant benefit in patients who had received prior BCG or chemotherapy (p⬍0.001). Recurrence rates measured at 9 –12 months were significantly lower overall with BL: 34.5% BL vs 45.4% WL (p⫽0.006, risk ratio⫽0.781). Risk ratios for recurrence were also lower in the sub-groups of patients with T1 or CIS (p⫽0.052, RR⫽0.696), and those with Ta (p⫽0.004, RR⫽0.804). CONCLUSIONS: This meta-analysis confirmed that BL cystoscopy with hexaminolevulinate added to WL cystoscopy significantly assists the detection of bladder tumors at both a patient and tumor level. The benefit of improved detection with BL cystoscopy led to improved clinical outcomes by reducing recurrence rates at 9 –12 months. Source of Funding: None