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Lymphovascular Invasion in Transurethral Resection Specimens as Predictor of Progression and Metastasis in Patients With Newly Diagnosed T1 Bladder Urothelial Cancer
Lymphovascular Invasion in Transurethral Resection Specimens as Predictor of Progression and Metastasis in Patients With Newly Diagnosed T1 Bladder Urothelial Cancer Kang Su Cho, Ho Kyung Seo, Jae Young Joung, Weon Seo Park, Jae Y. Ro, Kyung Seok Han, Jinsoo Chung and Kang Hyun Lee* From the Urologic Oncology Clinic (KSC, HKS, JYJ, KSH, JC, KHL) and Department of Pathology (WSP), Center for Specific Organs Cancer, National Cancer Center, Goyang, Korea, and Department of Pathology, Methodist Hospital and Research Institute, Weill Medical College of Cornell University (JYR), Houston, Texas
Purpose: We evaluated the clinical significance of lymphovascular invasion in transurethral resection of bladder tumor specimens in patients with newly diagnosed T1 urothelial carcinoma of the bladder. Materials and Methods: Enrolled in the study were 118 patients with newly diagnosed T1 urothelial carcinoma of the bladder who underwent transurethral resection of bladder tumor between 2001 and 2007. Patient records were retrieved from a prospectively maintained bladder cancer database. We evaluated the correlation between lymphovascular invasion and other clinicopathological features, and the impact of lymphovascular invasion on disease recurrence, disease progression and metastasis. Results: Lymphovascular invasion was histologically confirmed in 33 patients (28.0%). While lymphovascular invasion correlated with tumor grade (p ⫽ 0.002), it was not associated with gender, age, bladder tumor history, tumor size, multiplicity or concomitant carcinoma in situ. Recurrence, progression and metastasis developed in 45 (38.1%), 19 (16.1%) and 10 patients (8.5%), respectively. Univariate analysis showed that lymphovascular invasion was marginally associated with recurrence and significantly associated with progression (p ⫽ 0.011) and metastasis (p ⫽ 0.019). Multivariate Cox proportional hazards analysis revealed that recurrence was significantly associated with lymphovascular invasion (p ⫽ 0.029), and with bladder tumor history (p ⬍0.001), tumor size (p ⫽ 0.031) and multiplicity (p ⫽ 0.043). Lymphovascular invasion was the only independent prognostic factor associated with progression (p ⫽ 0.016). Conclusions: In patients with newly diagnosed T1 urothelial carcinoma of the bladder lymphovascular invasion in transurethral resection of bladder tumor specimens predicts disease progression and metastasis.
Abbreviations and Acronyms LVI ⫽ lymphovascular invasion TUR ⫽ transurethral resection TURBT ⫽ TUR of bladder tumor Submitted for publication April 6, 2009. Study received National Cancer Center institutional review board approval. * Correspondence: Urologic Oncology Clinic, National Cancer Center, 111 Jungbalsan-ro, Ilsandonggu, Goyang-si, Gyeonggi-do, 410-769, Republic of Korea (telephone: ⫹82-31-920-1676; FAX: ⫹82-31920-1790; e-mail: [email protected]).
For another article on a related topic see page 2932.
Key Words: urinary bladder; carcinoma, transitional cell; lymphatic metastasis; neoplasm invasiveness; urothelium UROTHELIAL carcinoma of the bladder can present as a muscle invasive or nonmuscle invasive lesion. Approximately 75% of patients present with nonmuscle invasive tumors limited to the mucosa or lamina propria. For non-
muscle invasive bladder tumors the probability of recurrence after TURBT at 1 year is 15% to 70% and the probability of progression at 5 years is 7% to 40%.1,2 Prior radical cystectomy series showed a LVI incidence of 30% to 50%
0022-5347/09/1826-2625/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 182, 2625-2631, December 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.08.083
www.jurology.com
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LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
in cases of urothelial carcinoma of the bladder.3–9 LVI is independently associated with overall, cancer specific and recurrence-free survival.4,6,7,9 Although some studies failed to show that LVI has a statistically significant impact on prognosis on multivariate analysis,3,5,8 LVI is generally considered a poor prognostic feature in patients with muscle invasive bladder cancer after radical surgery. Lopez and Angulo first noted that vascular invasion in TURBT surgical specimens of T1 bladder cancer is an independent prognostic factor.10 However, Larsen et al contradicted this finding.11 There are limited data on the clinical significance of LVI in TURBT specimens in patients with nonmuscle invasive bladder cancer. Thus, the clinical significance of LVI for nonmuscle invasive bladder cancer remains an open issue. We evaluated the clinical significance of LVI in patients with newly diagnosed T1 urothelial carcinoma of the bladder.
MATERIALS AND METHODS Study Population This study was approved by the National Cancer Center institutional review board. We reviewed archived data on consecutive patients newly diagnosed with T1 bladder cancer between 2001 and 2007 in the prospectively maintained National Cancer Center bladder cancer database. Patients with concomitant urothelial carcinoma of the upper urinary tract or nonurothelial carcinoma histology were excluded. A total of 118 patients with newly diagnosed T1 urothelial carcinoma of the bladder were enrolled in this study, of whom 101 (85.6%) were male and 21 (17.8%) had a history of Ta bladder tumor. Median patient age was 67 years (range 39 to 91) and median followup was 35 months (range 12 to 89).
A
Treatment and Data Collection All patients initially underwent TURBT. Repeat TURBT was done in 31 patients (26.3%) at surgeon discretion 2 to 6 weeks after initial surgery. Indications for repeat TURBT were an absent muscularis propria in initial TURBT specimens, suspicion of residual tumor and referral after initial TURBT was done elsewhere. The goal of repeat TURBT was to provide a wide resection margin and deep tumor removal to achieve complete resection of suspected residual tumor. A total of 100 patients (84.7%) underwent intravesical therapy after TURBT. Intravesical therapy consisted of a 6-week course of mitomycin C in 65 patients, a 6-week course of bacillus Calmette-Guerin in 27 and an 8-week course of epirubicin in 8. Systemic chemotherapy was recommended in patients with multifocal LVI and the final decision on chemotherapy was based on a combination of factors, including coexisting conditions, and patient ability and willingness to comply. Two or 3 cycles of cisplatin based chemotherapy were administered in 11 patients (9.3%), including a gemcitabine plus cisplatin regimen in 5, and methotrexate, vinblastine and doxorubicin plus cisplatin in 6. Subsequently radical cystectomy and pelvic lymphadenectomy after TURBT were done in 4 patients (3.4%). Followup was relatively uniform. Surveillance cystoscopy and urinary cytology were done at 3-month intervals in the first 2 years, at 6-month intervals in the next 3 years and annually thereafter. Generally abdominopelvic computerized tomography and chest radiography were done at 6 to 12-month intervals. Patient clinical and pathological features, and followup information were retrieved from the database. T stage was determined using the 2002 American Joint Committee on Cancer TNM staging system and histological grade was determined with the WHO system. Routine LVI evaluations were done. LVI was considered present only when tumor cells were unequivocally noted within or attached to the wall of a vascular or lymphatic space on hematoxylin and eosin stained sections. Multiple serial sections
B
Figure 1. LVI in representative cases (A and B) of T1 bladder urothelial carcinoma. H & E, reduced from ⫻200 (A and B) and ⫻400 (insets).
LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
were used in doubtful cases and in cases of aggressive tumors. Two independent uropathologists (WSP and JYR) reviewed hematoxylin and eosin stained slides. Figure 1 shows representative LVI cases.
Table 1. Data on 118 patients with newly diagnosed bladder T1 urothelial carcinoma, and associations between LVI and other features No. LVI (%)
Statistical Analysis Relations between LVI and other clinicopathological features were examined using the chi-square test. We examined the impact of LVI on disease recurrence, progression and metastasis. Disease progression was defined as muscularis propria invasion by urothelial carcinoma and/or as new onset metastatic disease. Univariate and multivariate Cox proportional hazards models were used for survival analysis. Survival curves were generated using the Kaplan-Meier method and the log rank test was done to determine the significance of differences between survival curves. Time to disease recurrence, progression and metastasis were defined as the interval from the date of initial diagnosis. SPSS® for Windows®, version 12.0 was used for statistical analysis with 2-sided p ⬍0.05 considered significant.
RESULTS LVl vs Other Features LVI was histologically confirmed in 33 patients (28.0%) with newly diagnosed T1 urothelial carcinoma of the bladder. Of these tumors 23 were grade 3 and 10 were grade 2 but there was no grade 1 tumor with LVI. LVI was associated with tumor grade (p ⫽ 0.003) but not with gender, age, bladder tumor history, tumor size, multiplicity or concomitant carcinoma in situ (p ⬎0.05, table 1). LVI Impact on Recurrence, Progression and Metastasis Disease recurrence, progression and metastasis developed in 45 (38.1%), 19 (16.1%) and 10 patients (8.5%), respectively. On univariate Cox proportional hazards analysis bladder tumor history (p ⬍0.001), tumor size (p ⫽ 0.026) and tumor number (p ⫽ 0.004) significantly influenced time to disease recurrence. LVI (p ⫽ 0.086) and intravesical therapy (p ⫽ 0.069) influenced bladder recurrence with borderline significance. LVI also significantly predicted disease progression and metastasis (p ⫽ 0.011 and 0.019, respectively, table 2 and fig. 2). Multivariate Cox proportional hazards analysis revealed that disease recurrence was significantly associated with LVI (p ⫽ 0.029), bladder tumor history (p ⬍0.001), tumor size (p ⫽ 0.031) and multiplicity (p ⫽ 0.043). LVI was the only independent prognostic factor associated with disease progression (HR 3.065, p ⫽ 0.016, table 3). However, the number of metastatic events was too small for multivariate analysis.
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Gender: M F Age: Less than 65 65 or Greater Bladder tumor history: No Yes Tumor size (cm): Less than 3 3 or Greater No. tumors: Less than 4 4 or Greater Tumor grade: 1 2 3 Carcinoma in situ: No Yes Repeat transurethral resection: No Yes Intravesical therapy: No Yes Systemic chemotherapy: No Yes Disease recurrence: No Yes Disease progression: No Yes Distant metastasis: No Yes Totals
No. Pts (%)
No
Yes
101 (85.6) 17 (14.4)
73 (85.9) 12 (14.1)
28 (84.8) 5 (15.2)
41 (34.7) 77 (65.3)
28 (32.9) 57 (67.1)
13 (39.4) 20 (60.6)
97 (82.2) 21 (17.8)
70 (82.4) 15 (17.6)
27 (81.8) 6 (18.2)
70 (59.3) 48 (40.7)
50 (58.8) 35 (41.2)
20 (60.6) 13 (39.4)
57 (48.3) 61 (51.7)
40 (47.1) 45 (52.9)
17 (51.5) 16 (48.5)
3 (2.5) 60 (50.8) 55 (46.6)
3 (3.5) 50 (58.8) 32 (37.6)
0 10 (30.3) 23 (69.7)
113 (95.8) 5 (4.2)
82 (96.5) 3 (3.5)
31 (93.9) 2 (6.1)
87 (73.7) 31 (26.3)
65 (76.5) 20 (23.5)
22 (66.7) 11 (33.3)
18 (15.3) 100 (84.7)
7 (8.2) 78 (91.8)
11 (33.3) 22 (66.7)
107 (90.7) 11 (9.3)
85 (100) 0
22 (66.7) 11 (33.3)
73 (61.9) 45 (38.1)
56 (65.9) 29 (34.1)
17 (51.5) 16 (48.5)
99 (83.9) 19 (16.1)
76 (89.4) 9 (10.6)
23 (69.7) 10 (30.3)
108 (91.5) 10 (8.5)
81 (95.3) 4 (4.7)
27 (81.8) 6 (18.2)
118 (100)
85 (72.0)
33 (28.0)
p Value 0.886
0.509
0.946
0.944
0.664
0.002
0.618
0.277
0.001
⬍0.001
0.149
0.009
0.018
DISCUSSION Our study shows that LVI predicts disease progression and metastasis in patients with newly diagnosed T1 bladder cancer. These findings concur with the study by Lopez and Angulo, in which multivariate analysis revealed that LVI in TURBT surgical specimens of T1 bladder cancer significantly influences survival and high grade neoplasms greater than 5 cm without a papillary configuration are associated with vascular invasion.10 Andius et al found that a solid tumor pattern and vascular invasion are independent prognostic factors of progression and disease specific survival.12 However, Larsen et al
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LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
Table 2. Univariate Cox proportional hazards model of bladder recurrence, disease progression and metastasis Recurrence
Gender (male vs female*) Age (65 or greater vs less than 65*) Bladder tumor history (yes vs no*) Tumor size (3 or greater vs less than 3 cm*) No. tumors (4 or greater vs less than 4*) Tumor grade (3 vs 1, 2*) Carcinoma in situ (yes vs no*) LVI (yes vs no*) Repeat TUR (no vs yes*) Intravesical therapy (no vs yes*) Systemic chemotherapy (no vs yes*)
Progression
Metastasis
HR (95% CI)
p Value
HR (95% CI)
p Value
HR (95% CI)
p Value
2.089 (0.748–5.834) 1.022 (0.550–1.900) 3.378 (1.806–6.317) 1.948 (1.083–3.503) 2.537 (1.348–4.776) 1.203 (0.670–2.158) 1.176 (0.284–4.877) 1.686 (0.901–3.022) 0.710 (0.371–1.356) 1.976 (0.949–4.115) 0.418 (0.194–0.898)
0.160 0.945 ⬍0.001 0.026 0.004 0.536 0.823 0.086 0.299 0.069 0.025
1.397 (0.323–6.048) 0.961 (0.378–2.444) 1.539 (0.508–4.331) 2.535 (0.995–6.459) 1.508 (0.603–3.769) 1.538 (0.618–3.827) 2.548 (0.326–19.939) 3.266 (1.316–8.105) 0.615 (0.232–1.631) 1.670 (0.552–5.049) 0.403 (0.132–1.225)
0.655 0.933 0.446 0.051 0.379 0.355 0.373 0.011 0.329 0.364 0.109
1.477 (0.187–11.664) 0.892 (0.251–3.171) 2.415 (0.621–9.385) 2.124 (0.597–7.554) 1.027 (0.296–3.560) 1.723 (0.485–6.116) 4.343 (0.520–36.255) 4.583 (1.278–16.438) 1.181 (0.249–5.599) 1.532 (0.193–12.145) 0.434 (0.090–2.098)
0.711 0.860 0.203 0.245 0.966 0.400 0.175 0.019 0.834 0.686 0.299
* Referent.
conclusions on prognostic values are based on univariate analysis alone.3,5,8 Several groups compared the prognostic values of lymphatic and blood vessel invasion,3,6,9,14 of which 2 concluded that only blood vessel invasion is an independent prognostic factor.6,9 Lotan et al maintained that the prognostic significance of LVI is only evident in lymph node negative cases.4 Nonetheless, information on the clinical significance of LVI in TURBT specimens in patients with nonmuscle invasive bladder cancer is sparse. Previous studies show a 10% to 25% LVI rate in T1 bladder cancer cases10,12,14,15 but in our series histologically confirmed LVI was found in 28.0% of cases, which to our knowledge is the highest value reported to date. However, Kakizoe et al reported a 25.0% lymphatic invasion rate and a 13.8% vascular invasion rate.14 Given that lymphatic and vascular invasion possibly present together, the prevalence of LVI in that study would have been 25% or greater. In our series the higher prevalence of LVI in T1 bladder can-
maintained that LVI in T1 bladder cancer does not necessarily portend a poor prognosis.11 Metastasis is a complex multistep process.13 Malignant cells must first escape from the primary tumor, invade surrounding tissues and enter the lymphatic or vascular circulation. Thus, attempts have been made to identify correlations between prognosis and LVI for various malignancies. For bladder cancer evidence on the clinical significance of LVI is increasing and recent cystectomy series have reinforced the significance of LVI for urothelial carcinoma of the bladder. Most series show that LVI correlates with T stage and tumor grade.3,4,6,10 LVI in cystectomy specimens is significantly associated with lymph node metastasis.4 LVI is generally considered a poor prognostic feature in patients with muscle invasive bladder cancer after radical cystectomy and LVI in surgical specimens is independently associated with overall, cancer specific and recurrence-free survival.4,6,7,9 However, some issues have yet to be resolved. In some studies
A
XUW
XUW
LV invasion ( )
LV invasion ( )
LV invasion ( ) WU]
LV invasion (+)
WU[
WUY
WU_
WU]
Metastasis-free survival
WU_
Progression-free survival
Disease recurrence-free survival
C
B XUW
LV invasion (+)
WU[
WUY
W
YW
[W
]W
_W
XWW
45 11
22 5
13 -
LV invasion (+) WU[
WUW W
YW
[W
]W
_W
XWW
W
YW
3 -
Number at risk LVI (-) 85 LVI (+) 33
62 16
25 10
15 -
[W
]W
_W
Follow-up (months)
Follow-up (months)
Follow-up (months) Number at risk LVI (-) 85 LVI (+) 33
WU]
WUY
WUW
WUW
WU_
4 -
Number at risk LVI (-) 85 LVI (+) 33
64 17
29 11
15 -
Figure 2. Disease recurrence-free (A), progression-free (B) and metastasis-free (C) survival curves by LVI
4 -
XWW
LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
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Table 3. Multivariate Cox proportional hazards model of disease recurrence and progression Recurrence
Bladder tumor history (yes vs no*) Tumor size (3 or greater vs less than 3 cm*) No. tumors (4 or greater vs less than 4*) LVI (yes vs no*) Intravesical therapy (no vs yes*)
Progression
HR (95% CI)
p Value
3.405 (1.738–6.672) 1.995 (1.064–3.741) 1.972 (1.021–3.811) 2.016 (1.114–3.903) 1.095 (0.483–2.484)
⬍0.001 0.031 0.043 0.029 0.828
HR (95% CI)
p Value
2.344 (0.918–5.984)
0.075
3.065 (1.233–7.620)
0.016
* Referent.
cer cases may be due to the fact that our cancer center is a tertiary referral center and, thus, the proportion of aggressive bladder tumors could well have been greater than normally observed. However, the most important reason for this higher prevalence is likely to be that study surgeons and pathologists were required by protocol to routinely evaluate LVI. Also, multiple serial sections were added in patients suspected of having an aggressive tumor. Although it is generally accepted that LVI is an indicator of bladder cancer aggressiveness, uncertainty remains concerning the impact of LVI on staging and therapeutic decision making, primarily because of its questionable reproducibility. These reproducibility issues are likely caused by the different histological criteria used by pathologists to identify LVI.16 Thus, we suggest that standard diagnostic criteria for LVI are urgently required and the potential usefulness of subsidiary immunohistochemical staining studies be examined in this context. Another equally problematic issue is optimal treatment for nonmuscle invasive bladder cancer with LVI, although intravesical instillation, radical cystectomy, systemic chemotherapy and combinations of the 3 methods are obvious possibilities. Based on the assumption that undetectable micrometastasis may be present in patients with LVI we consider systemic chemotherapy a reasonable option and preferred this approach in recent years. In the current study 11 of the 33 patients with LVI underwent 2 or 3 cycles of cisplatin based chemotherapy after TURBT. Unfortunately due to limited cohort size and relatively short followup we could not draw conclusions on the efficacy of systemic chemotherapy. Nevertheless, no significant difference was found in patients who did and did not undergo adjuvant systemic chemotherapy in terms of time to disease recurrence, progression or metastasis. Moreover, there is a real risk that a number of patients without evidence of metastasis may have been over treated and the opportunity to use alternate curative options such as radical cystectomy may have been missed in others.
Radical cystectomy with pelvic lymphadenectomy may be a suitable option because it controls micrometastasis in pelvic lymph nodes and undetected tumor foci in bladder walls. However, it is uncertain whether radical surgery could improve oncological outcomes in these patients. Several groups concluded that bacillus Calmette-Guerin treatment may produce favorable outcomes in patients with high risk, nonmuscle invasive bladder cancer cases17,18 but supporting data are limited in patients with LVI. Thus, we suggest that a large, well designed, prospective study with long-term followup be done to investigate potential treatment options for nonmuscle invasive bladder cancer with LVI. This study has several limitations. We determined LVI based on hematoxylin and eosin staining, not by immunohistochemical staining. This may have contributed to LVI overestimation since lymphovascular invasion may be misdiagnosed in hematoxylin and eosin stained specimens.11 Another limitation is that repeat TURBT was done selectively, introducing a risk of under staging. However, our standard procedure requires that initial TURBT be performed aggressively to obtain sufficient muscle tissue. Repeat TURBT was done in cases without muscularis propria in initial TURBT specimens with a suspicion of residual tumor and in cases referred after initial TURBT was done elsewhere. Thus, we believe that the risk of under staging was minimized.
CONCLUSIONS Our study shows that LVI in TURBT specimens is significantly associated with disease recurrence in patients with newly diagnosed T1 urothelial carcinoma of the bladder and it can predict disease progression and metastasis. Thus, we advocate that LVI in TURBT specimens be added to pathological reports and the histological criteria used by pathologists to identify LVI be standardized. Moreover, treatment in these patients remains to be determined. Thus, a well designed study is warranted to identify optimal treatment options.
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LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
REFERENCES 1. Allard P, Bernard P, Fradet Y et al: The early clinical course of primary Ta and T1 bladder cancer: a proposed prognostic index. Br J Urol 1998; 81: 692. 2. Kurth KH, Denis L, Bouffioux C et al: Factors affecting recurrence and progression in superficial bladder tumours. Eur J Cancer 1995; 31A: 1840. 3. Harada K, Sakai I, Hara I et al: Prognostic significance of vascular invasion in patients with bladder cancer who underwent radical cystectomy. Int J Urol 2005; 12: 250. 4. Lotan Y, Gupta A, Shariat SF et al: Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. J Clin Oncol 2005; 23: 6533.
in urothelial bladder cancer treated with radical cystectomy. J Urol 2003; 169: 955.
pattern (solid or papillary) and vascular invasion more important than depth of invasion. Urology 2007; 70: 758.
7. Quek ML, Stein JP, Nichols PW et al: Prognostic significance of lymphovascular invasion of bladder cancer treated with radical cystectomy. J Urol 2005; 174: 103.
13. Fidler IJ: Critical determinants of cancer metastasis: rationale for therapy. Cancer Chemother Pharmacol, suppl., 1999; 43: S3.
8. Hara S, Miyake H, Fujisawa M et al: Prognostic variables in patients who have undergone radical cystectomy for transitional cell carcinoma of the bladder. Jpn J Clin Oncol 2001; 31: 399.
14. Kakizoe T, Tobisu K, Mizutani T et al: Analysis by step sectioning of early invasive bladder cancer with special reference to G3.pT1 disease. Jpn J Cancer Res 1992; 83: 1354.
9. Hong SK, Kwak C, Jeon HG et al: Do vascular, lymphatic, and perineural invasion have prognostic implications for bladder cancer after radical cystectomy? Urology 2005; 65: 697. 10. Lopez JI and Angulo JC: The prognostic significance of vascular invasion in stage T1 bladder cancer. Histopathology 1995; 27: 27.
5. Bassi P, Ferrante GD, Piazza N et al: Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 1999; 161: 1494.
11. Larsen MP, Steinberg GD, Brendler CB et al: Use of Ulex europaeus agglutinin I (UEAI) to distinguish vascular and “pseudovascular” invasion in transitional cell carcinoma of bladder with lamina propria invasion. Mod Pathol 1990; 3: 83.
6. Leissner J, Koeppen C and Wolf HK: Prognostic significance of vascular and perineural invasion
12. Andius P, Johansson SL and Holmang S: Prognostic factors in stage T1 bladder cancer: tumor
15. Gohji K, Nomi M, Okamoto M et al: Conservative therapy for stage T1b, grade 3 transitional cell carcinoma of the bladder. Urology 1999; 53: 308. 16. Algaba F: Lymphovascular invasion as a prognostic tool for advanced bladder cancer. Curr Opin Urol 2006; 16: 367. 17. Lamm DL, Blumenstein BA, Crawford ED et al: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. N Engl J Med 1991; 325: 1205. 18. Cookson MS, Herr HW, Zhang ZF et al: The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 1997; 158: 62.
EDITORIAL COMMENT LVI is an adverse prognostic factor in bladder cancer cases and a harbinger of more aggressive disease, including occult metastasis. While it is best determined in radical cystectomy specimens, its presence in the TUR specimen has special value since it guides the urologist towards neoadjuvant chemotherapy before radical cystectomy. However, the prognostic significance of LVI for cT1 remains controversial. Part of this controversy is due to difficult identification of LVI in a limited tumor specimen. Retraction artifacts of stromal tissue surrounding tumor can mimic vascular invasion, leading to misclassification. Even in whole organ specimens some experts recommend reporting LVI only with the assistance of immunohistochemical staining for blood vessels. These authors found evidence of LVI in 28% of 118 patients with cT1 disease in the TURBT specimen in whom LVI was associated with disease progression and metastasis. Most patients did not undergo repeat TUR so that the incidence of under staging is unknown. The survival graphs do not diverge until about 20 months and followup in most patients was only 3 years. Moreover, the study highlights a potential for bias in evaluating pathological features such as LVI without standardized acquisition techniques. The authors reflect that multiple serial sections were added in patients suspected of having an aggressive tumor. It is possible that this
identified LVI better in patients with more aggressive tumors and biased results toward demonstrating LVI as a poor prognostic feature. Lastly, despite small numbers it would have been interesting and possibly revealing if the authors had broken down recurrence and metastasis rates based on therapy offered to the patient. Unfortunately despite this report the question that remains unanswered is whether LVI detected on cT1 specimens (which have been adequately staged) mandate radical cystectomy with neoadjuvant chemotherapy or whether bladder conservation may be considered. At our institution we offer these patients repeat resection. When repeat resection is negative and the initial tumor was only focally invasive into the lamina propria, we offer them bladder conservation therapy. However, when there is repeat T1 disease or extensive lamina propria invasion, we offer neoadjuvant therapy followed by radical cystectomy as a preferred option in our patients. The real answer would be obtained only from a well stratified, prospective, randomized trial. We invite readers with like minds to collaborate in performing such a trial. Ashish M. Kamat and Robert Svatek Department of Urology M. D. Anderson Cancer Center Houston, Texas
LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
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REPLY BY AUTHORS Controversy remains in regard to pathological determination of LVI in cystectomy specimens. Furthermore, LVI in TUR specimens is even more controversial as a consensus guideline has not been established for its diagnosis. There are several important issues, ie whether pathologists should describe the presence of LVI and whether immunohistochemical staining is mandatory to document LVI. In fact, most of the published studies have evaluated LVI based on hematoxylin and eosin staining without any special studies (reference 16 in article). It is our hope that more active discussion regarding these issues will follow and a standardized guideline will be adopted in the near future. How to manage T1 bladder cancer with LVI is
also important and might cause a significant change in the treatment algorithms for nonmuscle invasive bladder cancer. Currently the true implication of LVI in TUR specimens is not fully understood. Theoretically LVI can be a proxy of locally aggressive and/or systemic disease. At our institute we have focused more on the possibility of systemic disease. Thus, we prefer systemic chemotherapy and reserve radical cystectomy until muscle invasive disease develops. However, it is not possible to demonstrate the oncological results of our experience due to the small cohort size and relatively short followup. For this reason we welcome the proposal for a prospective, randomized study, which we consider to be timely and appropriate.
Purpose: We evaluated the clinical significance of lymphovascular invasion in transurethral resection of bladder tumor specimens in patients with newly diagnosed T1 urothelial carcinoma of the bladder. Materials and Methods: Enrolled in the study were 118 patients with newly diagnosed T1 urothelial carcinoma of the bladder who underwent transurethral resection of bladder tumor between 2001 and 2007. Patient records were retrieved from a prospectively maintained bladder cancer database. We evaluated the correlation between lymphovascular invasion and other clinicopathological features, and the impact of lymphovascular invasion on disease recurrence, disease progression and metastasis. Results: Lymphovascular invasion was histologically confirmed in 33 patients (28.0%). While lymphovascular invasion correlated with tumor grade (p ⫽ 0.002), it was not associated with gender, age, bladder tumor history, tumor size, multiplicity or concomitant carcinoma in situ. Recurrence, progression and metastasis developed in 45 (38.1%), 19 (16.1%) and 10 patients (8.5%), respectively. Univariate analysis showed that lymphovascular invasion was marginally associated with recurrence and significantly associated with progression (p ⫽ 0.011) and metastasis (p ⫽ 0.019). Multivariate Cox proportional hazards analysis revealed that recurrence was significantly associated with lymphovascular invasion (p ⫽ 0.029), and with bladder tumor history (p ⬍0.001), tumor size (p ⫽ 0.031) and multiplicity (p ⫽ 0.043). Lymphovascular invasion was the only independent prognostic factor associated with progression (p ⫽ 0.016). Conclusions: In patients with newly diagnosed T1 urothelial carcinoma of the bladder lymphovascular invasion in transurethral resection of bladder tumor specimens predicts disease progression and metastasis.
Abbreviations and Acronyms LVI ⫽ lymphovascular invasion TUR ⫽ transurethral resection TURBT ⫽ TUR of bladder tumor Submitted for publication April 6, 2009. Study received National Cancer Center institutional review board approval. * Correspondence: Urologic Oncology Clinic, National Cancer Center, 111 Jungbalsan-ro, Ilsandonggu, Goyang-si, Gyeonggi-do, 410-769, Republic of Korea (telephone: ⫹82-31-920-1676; FAX: ⫹82-31920-1790; e-mail: [email protected]).
For another article on a related topic see page 2932.
Key Words: urinary bladder; carcinoma, transitional cell; lymphatic metastasis; neoplasm invasiveness; urothelium UROTHELIAL carcinoma of the bladder can present as a muscle invasive or nonmuscle invasive lesion. Approximately 75% of patients present with nonmuscle invasive tumors limited to the mucosa or lamina propria. For non-
muscle invasive bladder tumors the probability of recurrence after TURBT at 1 year is 15% to 70% and the probability of progression at 5 years is 7% to 40%.1,2 Prior radical cystectomy series showed a LVI incidence of 30% to 50%
0022-5347/09/1826-2625/0 THE JOURNAL OF UROLOGY® Copyright © 2009 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 182, 2625-2631, December 2009 Printed in U.S.A. DOI:10.1016/j.juro.2009.08.083
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LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
in cases of urothelial carcinoma of the bladder.3–9 LVI is independently associated with overall, cancer specific and recurrence-free survival.4,6,7,9 Although some studies failed to show that LVI has a statistically significant impact on prognosis on multivariate analysis,3,5,8 LVI is generally considered a poor prognostic feature in patients with muscle invasive bladder cancer after radical surgery. Lopez and Angulo first noted that vascular invasion in TURBT surgical specimens of T1 bladder cancer is an independent prognostic factor.10 However, Larsen et al contradicted this finding.11 There are limited data on the clinical significance of LVI in TURBT specimens in patients with nonmuscle invasive bladder cancer. Thus, the clinical significance of LVI for nonmuscle invasive bladder cancer remains an open issue. We evaluated the clinical significance of LVI in patients with newly diagnosed T1 urothelial carcinoma of the bladder.
MATERIALS AND METHODS Study Population This study was approved by the National Cancer Center institutional review board. We reviewed archived data on consecutive patients newly diagnosed with T1 bladder cancer between 2001 and 2007 in the prospectively maintained National Cancer Center bladder cancer database. Patients with concomitant urothelial carcinoma of the upper urinary tract or nonurothelial carcinoma histology were excluded. A total of 118 patients with newly diagnosed T1 urothelial carcinoma of the bladder were enrolled in this study, of whom 101 (85.6%) were male and 21 (17.8%) had a history of Ta bladder tumor. Median patient age was 67 years (range 39 to 91) and median followup was 35 months (range 12 to 89).
A
Treatment and Data Collection All patients initially underwent TURBT. Repeat TURBT was done in 31 patients (26.3%) at surgeon discretion 2 to 6 weeks after initial surgery. Indications for repeat TURBT were an absent muscularis propria in initial TURBT specimens, suspicion of residual tumor and referral after initial TURBT was done elsewhere. The goal of repeat TURBT was to provide a wide resection margin and deep tumor removal to achieve complete resection of suspected residual tumor. A total of 100 patients (84.7%) underwent intravesical therapy after TURBT. Intravesical therapy consisted of a 6-week course of mitomycin C in 65 patients, a 6-week course of bacillus Calmette-Guerin in 27 and an 8-week course of epirubicin in 8. Systemic chemotherapy was recommended in patients with multifocal LVI and the final decision on chemotherapy was based on a combination of factors, including coexisting conditions, and patient ability and willingness to comply. Two or 3 cycles of cisplatin based chemotherapy were administered in 11 patients (9.3%), including a gemcitabine plus cisplatin regimen in 5, and methotrexate, vinblastine and doxorubicin plus cisplatin in 6. Subsequently radical cystectomy and pelvic lymphadenectomy after TURBT were done in 4 patients (3.4%). Followup was relatively uniform. Surveillance cystoscopy and urinary cytology were done at 3-month intervals in the first 2 years, at 6-month intervals in the next 3 years and annually thereafter. Generally abdominopelvic computerized tomography and chest radiography were done at 6 to 12-month intervals. Patient clinical and pathological features, and followup information were retrieved from the database. T stage was determined using the 2002 American Joint Committee on Cancer TNM staging system and histological grade was determined with the WHO system. Routine LVI evaluations were done. LVI was considered present only when tumor cells were unequivocally noted within or attached to the wall of a vascular or lymphatic space on hematoxylin and eosin stained sections. Multiple serial sections
B
Figure 1. LVI in representative cases (A and B) of T1 bladder urothelial carcinoma. H & E, reduced from ⫻200 (A and B) and ⫻400 (insets).
LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
were used in doubtful cases and in cases of aggressive tumors. Two independent uropathologists (WSP and JYR) reviewed hematoxylin and eosin stained slides. Figure 1 shows representative LVI cases.
Table 1. Data on 118 patients with newly diagnosed bladder T1 urothelial carcinoma, and associations between LVI and other features No. LVI (%)
Statistical Analysis Relations between LVI and other clinicopathological features were examined using the chi-square test. We examined the impact of LVI on disease recurrence, progression and metastasis. Disease progression was defined as muscularis propria invasion by urothelial carcinoma and/or as new onset metastatic disease. Univariate and multivariate Cox proportional hazards models were used for survival analysis. Survival curves were generated using the Kaplan-Meier method and the log rank test was done to determine the significance of differences between survival curves. Time to disease recurrence, progression and metastasis were defined as the interval from the date of initial diagnosis. SPSS® for Windows®, version 12.0 was used for statistical analysis with 2-sided p ⬍0.05 considered significant.
RESULTS LVl vs Other Features LVI was histologically confirmed in 33 patients (28.0%) with newly diagnosed T1 urothelial carcinoma of the bladder. Of these tumors 23 were grade 3 and 10 were grade 2 but there was no grade 1 tumor with LVI. LVI was associated with tumor grade (p ⫽ 0.003) but not with gender, age, bladder tumor history, tumor size, multiplicity or concomitant carcinoma in situ (p ⬎0.05, table 1). LVI Impact on Recurrence, Progression and Metastasis Disease recurrence, progression and metastasis developed in 45 (38.1%), 19 (16.1%) and 10 patients (8.5%), respectively. On univariate Cox proportional hazards analysis bladder tumor history (p ⬍0.001), tumor size (p ⫽ 0.026) and tumor number (p ⫽ 0.004) significantly influenced time to disease recurrence. LVI (p ⫽ 0.086) and intravesical therapy (p ⫽ 0.069) influenced bladder recurrence with borderline significance. LVI also significantly predicted disease progression and metastasis (p ⫽ 0.011 and 0.019, respectively, table 2 and fig. 2). Multivariate Cox proportional hazards analysis revealed that disease recurrence was significantly associated with LVI (p ⫽ 0.029), bladder tumor history (p ⬍0.001), tumor size (p ⫽ 0.031) and multiplicity (p ⫽ 0.043). LVI was the only independent prognostic factor associated with disease progression (HR 3.065, p ⫽ 0.016, table 3). However, the number of metastatic events was too small for multivariate analysis.
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Gender: M F Age: Less than 65 65 or Greater Bladder tumor history: No Yes Tumor size (cm): Less than 3 3 or Greater No. tumors: Less than 4 4 or Greater Tumor grade: 1 2 3 Carcinoma in situ: No Yes Repeat transurethral resection: No Yes Intravesical therapy: No Yes Systemic chemotherapy: No Yes Disease recurrence: No Yes Disease progression: No Yes Distant metastasis: No Yes Totals
No. Pts (%)
No
Yes
101 (85.6) 17 (14.4)
73 (85.9) 12 (14.1)
28 (84.8) 5 (15.2)
41 (34.7) 77 (65.3)
28 (32.9) 57 (67.1)
13 (39.4) 20 (60.6)
97 (82.2) 21 (17.8)
70 (82.4) 15 (17.6)
27 (81.8) 6 (18.2)
70 (59.3) 48 (40.7)
50 (58.8) 35 (41.2)
20 (60.6) 13 (39.4)
57 (48.3) 61 (51.7)
40 (47.1) 45 (52.9)
17 (51.5) 16 (48.5)
3 (2.5) 60 (50.8) 55 (46.6)
3 (3.5) 50 (58.8) 32 (37.6)
0 10 (30.3) 23 (69.7)
113 (95.8) 5 (4.2)
82 (96.5) 3 (3.5)
31 (93.9) 2 (6.1)
87 (73.7) 31 (26.3)
65 (76.5) 20 (23.5)
22 (66.7) 11 (33.3)
18 (15.3) 100 (84.7)
7 (8.2) 78 (91.8)
11 (33.3) 22 (66.7)
107 (90.7) 11 (9.3)
85 (100) 0
22 (66.7) 11 (33.3)
73 (61.9) 45 (38.1)
56 (65.9) 29 (34.1)
17 (51.5) 16 (48.5)
99 (83.9) 19 (16.1)
76 (89.4) 9 (10.6)
23 (69.7) 10 (30.3)
108 (91.5) 10 (8.5)
81 (95.3) 4 (4.7)
27 (81.8) 6 (18.2)
118 (100)
85 (72.0)
33 (28.0)
p Value 0.886
0.509
0.946
0.944
0.664
0.002
0.618
0.277
0.001
⬍0.001
0.149
0.009
0.018
DISCUSSION Our study shows that LVI predicts disease progression and metastasis in patients with newly diagnosed T1 bladder cancer. These findings concur with the study by Lopez and Angulo, in which multivariate analysis revealed that LVI in TURBT surgical specimens of T1 bladder cancer significantly influences survival and high grade neoplasms greater than 5 cm without a papillary configuration are associated with vascular invasion.10 Andius et al found that a solid tumor pattern and vascular invasion are independent prognostic factors of progression and disease specific survival.12 However, Larsen et al
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LYMPHOVASCULAR INVASION AND T1 BLADDER UROTHELIAL CANCER
Table 2. Univariate Cox proportional hazards model of bladder recurrence, disease progression and metastasis Recurrence
Gender (male vs female*) Age (65 or greater vs less than 65*) Bladder tumor history (yes vs no*) Tumor size (3 or greater vs less than 3 cm*) No. tumors (4 or greater vs less than 4*) Tumor grade (3 vs 1, 2*) Carcinoma in situ (yes vs no*) LVI (yes vs no*) Repeat TUR (no vs yes*) Intravesical therapy (no vs yes*) Systemic chemotherapy (no vs yes*)
Progression
Metastasis
HR (95% CI)
p Value
HR (95% CI)
p Value
HR (95% CI)
p Value
2.089 (0.748–5.834) 1.022 (0.550–1.900) 3.378 (1.806–6.317) 1.948 (1.083–3.503) 2.537 (1.348–4.776) 1.203 (0.670–2.158) 1.176 (0.284–4.877) 1.686 (0.901–3.022) 0.710 (0.371–1.356) 1.976 (0.949–4.115) 0.418 (0.194–0.898)
0.160 0.945 ⬍0.001 0.026 0.004 0.536 0.823 0.086 0.299 0.069 0.025
1.397 (0.323–6.048) 0.961 (0.378–2.444) 1.539 (0.508–4.331) 2.535 (0.995–6.459) 1.508 (0.603–3.769) 1.538 (0.618–3.827) 2.548 (0.326–19.939) 3.266 (1.316–8.105) 0.615 (0.232–1.631) 1.670 (0.552–5.049) 0.403 (0.132–1.225)
0.655 0.933 0.446 0.051 0.379 0.355 0.373 0.011 0.329 0.364 0.109
1.477 (0.187–11.664) 0.892 (0.251–3.171) 2.415 (0.621–9.385) 2.124 (0.597–7.554) 1.027 (0.296–3.560) 1.723 (0.485–6.116) 4.343 (0.520–36.255) 4.583 (1.278–16.438) 1.181 (0.249–5.599) 1.532 (0.193–12.145) 0.434 (0.090–2.098)
0.711 0.860 0.203 0.245 0.966 0.400 0.175 0.019 0.834 0.686 0.299
* Referent.
conclusions on prognostic values are based on univariate analysis alone.3,5,8 Several groups compared the prognostic values of lymphatic and blood vessel invasion,3,6,9,14 of which 2 concluded that only blood vessel invasion is an independent prognostic factor.6,9 Lotan et al maintained that the prognostic significance of LVI is only evident in lymph node negative cases.4 Nonetheless, information on the clinical significance of LVI in TURBT specimens in patients with nonmuscle invasive bladder cancer is sparse. Previous studies show a 10% to 25% LVI rate in T1 bladder cancer cases10,12,14,15 but in our series histologically confirmed LVI was found in 28.0% of cases, which to our knowledge is the highest value reported to date. However, Kakizoe et al reported a 25.0% lymphatic invasion rate and a 13.8% vascular invasion rate.14 Given that lymphatic and vascular invasion possibly present together, the prevalence of LVI in that study would have been 25% or greater. In our series the higher prevalence of LVI in T1 bladder can-
maintained that LVI in T1 bladder cancer does not necessarily portend a poor prognosis.11 Metastasis is a complex multistep process.13 Malignant cells must first escape from the primary tumor, invade surrounding tissues and enter the lymphatic or vascular circulation. Thus, attempts have been made to identify correlations between prognosis and LVI for various malignancies. For bladder cancer evidence on the clinical significance of LVI is increasing and recent cystectomy series have reinforced the significance of LVI for urothelial carcinoma of the bladder. Most series show that LVI correlates with T stage and tumor grade.3,4,6,10 LVI in cystectomy specimens is significantly associated with lymph node metastasis.4 LVI is generally considered a poor prognostic feature in patients with muscle invasive bladder cancer after radical cystectomy and LVI in surgical specimens is independently associated with overall, cancer specific and recurrence-free survival.4,6,7,9 However, some issues have yet to be resolved. In some studies
A
XUW
XUW
LV invasion ( )
LV invasion ( )
LV invasion ( ) WU]
LV invasion (+)
WU[
WUY
WU_
WU]
Metastasis-free survival
WU_
Progression-free survival
Disease recurrence-free survival
C
B XUW
LV invasion (+)
WU[
WUY
W
YW
[W
]W
_W
XWW
45 11
22 5
13 -
LV invasion (+) WU[
WUW W
YW
[W
]W
_W
XWW
W
YW
3 -
Number at risk LVI (-) 85 LVI (+) 33
62 16
25 10
15 -
[W
]W
_W
Follow-up (months)
Follow-up (months)
Follow-up (months) Number at risk LVI (-) 85 LVI (+) 33
WU]
WUY
WUW
WUW
WU_
4 -
Number at risk LVI (-) 85 LVI (+) 33
64 17
29 11
15 -
Figure 2. Disease recurrence-free (A), progression-free (B) and metastasis-free (C) survival curves by LVI
4 -
XWW
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Table 3. Multivariate Cox proportional hazards model of disease recurrence and progression Recurrence
Bladder tumor history (yes vs no*) Tumor size (3 or greater vs less than 3 cm*) No. tumors (4 or greater vs less than 4*) LVI (yes vs no*) Intravesical therapy (no vs yes*)
Progression
HR (95% CI)
p Value
3.405 (1.738–6.672) 1.995 (1.064–3.741) 1.972 (1.021–3.811) 2.016 (1.114–3.903) 1.095 (0.483–2.484)
⬍0.001 0.031 0.043 0.029 0.828
HR (95% CI)
p Value
2.344 (0.918–5.984)
0.075
3.065 (1.233–7.620)
0.016
* Referent.
cer cases may be due to the fact that our cancer center is a tertiary referral center and, thus, the proportion of aggressive bladder tumors could well have been greater than normally observed. However, the most important reason for this higher prevalence is likely to be that study surgeons and pathologists were required by protocol to routinely evaluate LVI. Also, multiple serial sections were added in patients suspected of having an aggressive tumor. Although it is generally accepted that LVI is an indicator of bladder cancer aggressiveness, uncertainty remains concerning the impact of LVI on staging and therapeutic decision making, primarily because of its questionable reproducibility. These reproducibility issues are likely caused by the different histological criteria used by pathologists to identify LVI.16 Thus, we suggest that standard diagnostic criteria for LVI are urgently required and the potential usefulness of subsidiary immunohistochemical staining studies be examined in this context. Another equally problematic issue is optimal treatment for nonmuscle invasive bladder cancer with LVI, although intravesical instillation, radical cystectomy, systemic chemotherapy and combinations of the 3 methods are obvious possibilities. Based on the assumption that undetectable micrometastasis may be present in patients with LVI we consider systemic chemotherapy a reasonable option and preferred this approach in recent years. In the current study 11 of the 33 patients with LVI underwent 2 or 3 cycles of cisplatin based chemotherapy after TURBT. Unfortunately due to limited cohort size and relatively short followup we could not draw conclusions on the efficacy of systemic chemotherapy. Nevertheless, no significant difference was found in patients who did and did not undergo adjuvant systemic chemotherapy in terms of time to disease recurrence, progression or metastasis. Moreover, there is a real risk that a number of patients without evidence of metastasis may have been over treated and the opportunity to use alternate curative options such as radical cystectomy may have been missed in others.
Radical cystectomy with pelvic lymphadenectomy may be a suitable option because it controls micrometastasis in pelvic lymph nodes and undetected tumor foci in bladder walls. However, it is uncertain whether radical surgery could improve oncological outcomes in these patients. Several groups concluded that bacillus Calmette-Guerin treatment may produce favorable outcomes in patients with high risk, nonmuscle invasive bladder cancer cases17,18 but supporting data are limited in patients with LVI. Thus, we suggest that a large, well designed, prospective study with long-term followup be done to investigate potential treatment options for nonmuscle invasive bladder cancer with LVI. This study has several limitations. We determined LVI based on hematoxylin and eosin staining, not by immunohistochemical staining. This may have contributed to LVI overestimation since lymphovascular invasion may be misdiagnosed in hematoxylin and eosin stained specimens.11 Another limitation is that repeat TURBT was done selectively, introducing a risk of under staging. However, our standard procedure requires that initial TURBT be performed aggressively to obtain sufficient muscle tissue. Repeat TURBT was done in cases without muscularis propria in initial TURBT specimens with a suspicion of residual tumor and in cases referred after initial TURBT was done elsewhere. Thus, we believe that the risk of under staging was minimized.
CONCLUSIONS Our study shows that LVI in TURBT specimens is significantly associated with disease recurrence in patients with newly diagnosed T1 urothelial carcinoma of the bladder and it can predict disease progression and metastasis. Thus, we advocate that LVI in TURBT specimens be added to pathological reports and the histological criteria used by pathologists to identify LVI be standardized. Moreover, treatment in these patients remains to be determined. Thus, a well designed study is warranted to identify optimal treatment options.
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REFERENCES 1. Allard P, Bernard P, Fradet Y et al: The early clinical course of primary Ta and T1 bladder cancer: a proposed prognostic index. Br J Urol 1998; 81: 692. 2. Kurth KH, Denis L, Bouffioux C et al: Factors affecting recurrence and progression in superficial bladder tumours. Eur J Cancer 1995; 31A: 1840. 3. Harada K, Sakai I, Hara I et al: Prognostic significance of vascular invasion in patients with bladder cancer who underwent radical cystectomy. Int J Urol 2005; 12: 250. 4. Lotan Y, Gupta A, Shariat SF et al: Lymphovascular invasion is independently associated with overall survival, cause-specific survival, and local and distant recurrence in patients with negative lymph nodes at radical cystectomy. J Clin Oncol 2005; 23: 6533.
in urothelial bladder cancer treated with radical cystectomy. J Urol 2003; 169: 955.
pattern (solid or papillary) and vascular invasion more important than depth of invasion. Urology 2007; 70: 758.
7. Quek ML, Stein JP, Nichols PW et al: Prognostic significance of lymphovascular invasion of bladder cancer treated with radical cystectomy. J Urol 2005; 174: 103.
13. Fidler IJ: Critical determinants of cancer metastasis: rationale for therapy. Cancer Chemother Pharmacol, suppl., 1999; 43: S3.
8. Hara S, Miyake H, Fujisawa M et al: Prognostic variables in patients who have undergone radical cystectomy for transitional cell carcinoma of the bladder. Jpn J Clin Oncol 2001; 31: 399.
14. Kakizoe T, Tobisu K, Mizutani T et al: Analysis by step sectioning of early invasive bladder cancer with special reference to G3.pT1 disease. Jpn J Cancer Res 1992; 83: 1354.
9. Hong SK, Kwak C, Jeon HG et al: Do vascular, lymphatic, and perineural invasion have prognostic implications for bladder cancer after radical cystectomy? Urology 2005; 65: 697. 10. Lopez JI and Angulo JC: The prognostic significance of vascular invasion in stage T1 bladder cancer. Histopathology 1995; 27: 27.
5. Bassi P, Ferrante GD, Piazza N et al: Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. J Urol 1999; 161: 1494.
11. Larsen MP, Steinberg GD, Brendler CB et al: Use of Ulex europaeus agglutinin I (UEAI) to distinguish vascular and “pseudovascular” invasion in transitional cell carcinoma of bladder with lamina propria invasion. Mod Pathol 1990; 3: 83.
6. Leissner J, Koeppen C and Wolf HK: Prognostic significance of vascular and perineural invasion
12. Andius P, Johansson SL and Holmang S: Prognostic factors in stage T1 bladder cancer: tumor
15. Gohji K, Nomi M, Okamoto M et al: Conservative therapy for stage T1b, grade 3 transitional cell carcinoma of the bladder. Urology 1999; 53: 308. 16. Algaba F: Lymphovascular invasion as a prognostic tool for advanced bladder cancer. Curr Opin Urol 2006; 16: 367. 17. Lamm DL, Blumenstein BA, Crawford ED et al: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. N Engl J Med 1991; 325: 1205. 18. Cookson MS, Herr HW, Zhang ZF et al: The treated natural history of high risk superficial bladder cancer: 15-year outcome. J Urol 1997; 158: 62.
EDITORIAL COMMENT LVI is an adverse prognostic factor in bladder cancer cases and a harbinger of more aggressive disease, including occult metastasis. While it is best determined in radical cystectomy specimens, its presence in the TUR specimen has special value since it guides the urologist towards neoadjuvant chemotherapy before radical cystectomy. However, the prognostic significance of LVI for cT1 remains controversial. Part of this controversy is due to difficult identification of LVI in a limited tumor specimen. Retraction artifacts of stromal tissue surrounding tumor can mimic vascular invasion, leading to misclassification. Even in whole organ specimens some experts recommend reporting LVI only with the assistance of immunohistochemical staining for blood vessels. These authors found evidence of LVI in 28% of 118 patients with cT1 disease in the TURBT specimen in whom LVI was associated with disease progression and metastasis. Most patients did not undergo repeat TUR so that the incidence of under staging is unknown. The survival graphs do not diverge until about 20 months and followup in most patients was only 3 years. Moreover, the study highlights a potential for bias in evaluating pathological features such as LVI without standardized acquisition techniques. The authors reflect that multiple serial sections were added in patients suspected of having an aggressive tumor. It is possible that this
identified LVI better in patients with more aggressive tumors and biased results toward demonstrating LVI as a poor prognostic feature. Lastly, despite small numbers it would have been interesting and possibly revealing if the authors had broken down recurrence and metastasis rates based on therapy offered to the patient. Unfortunately despite this report the question that remains unanswered is whether LVI detected on cT1 specimens (which have been adequately staged) mandate radical cystectomy with neoadjuvant chemotherapy or whether bladder conservation may be considered. At our institution we offer these patients repeat resection. When repeat resection is negative and the initial tumor was only focally invasive into the lamina propria, we offer them bladder conservation therapy. However, when there is repeat T1 disease or extensive lamina propria invasion, we offer neoadjuvant therapy followed by radical cystectomy as a preferred option in our patients. The real answer would be obtained only from a well stratified, prospective, randomized trial. We invite readers with like minds to collaborate in performing such a trial. Ashish M. Kamat and Robert Svatek Department of Urology M. D. Anderson Cancer Center Houston, Texas
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REPLY BY AUTHORS Controversy remains in regard to pathological determination of LVI in cystectomy specimens. Furthermore, LVI in TUR specimens is even more controversial as a consensus guideline has not been established for its diagnosis. There are several important issues, ie whether pathologists should describe the presence of LVI and whether immunohistochemical staining is mandatory to document LVI. In fact, most of the published studies have evaluated LVI based on hematoxylin and eosin staining without any special studies (reference 16 in article). It is our hope that more active discussion regarding these issues will follow and a standardized guideline will be adopted in the near future. How to manage T1 bladder cancer with LVI is
also important and might cause a significant change in the treatment algorithms for nonmuscle invasive bladder cancer. Currently the true implication of LVI in TUR specimens is not fully understood. Theoretically LVI can be a proxy of locally aggressive and/or systemic disease. At our institute we have focused more on the possibility of systemic disease. Thus, we prefer systemic chemotherapy and reserve radical cystectomy until muscle invasive disease develops. However, it is not possible to demonstrate the oncological results of our experience due to the small cohort size and relatively short followup. For this reason we welcome the proposal for a prospective, randomized study, which we consider to be timely and appropriate.