Originally published as JCO Early Release 10.1200/JCO.2005.05.033 on August 29 2005

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Lymphovascular Invasion As an Independent Predictor of Recurrence and Survival in Node-Negative Bladder Cancer Remains to Be Proven

Pathology Department, Memorial Sloan-Kettering Cancer Center

Radical cystectomy is commonly the treatment of choice for patients with muscularis propria–invasive urothelial carcinoma. Unfortunately, up to 40% of patients whose disease is confined to the bladder wall will develop tumor recurrence; virtually all of them will die as a result of the disease. Thus, it is imperative that we find additional markers (clinical, pathologic, or molecular) to predict adverse clinical events in these patients. The retrospective multi-institutional study reported in this issue of the Journal of Clinical Oncology¹ suggests that lymphovascular invasion is such a marker, given that its presence was found to be associated independently with local and distant recurrence as well as cause-specific and overall survival in lymph node–negative patients. This study was based on 750 patients who underwent cystectomy for "usual" urothelial carcinoma and in whom lymphovascular invasion status was determined through review of the pathology reports. The final cohort was selected from a series of 958 patients who underwent cystectomy for bladder cancer at one of three participating medical institutions between 1984 and 2003. Exclusion criteria included incomplete data sets (120 patients), non–transitional-cell histology (62 patients), and lack of information on lymphovascular status (26 patients).

The results, if confirmed in additional large, well-designed—and preferably prospective—studies, suggest that lymphovascular invasion should be included in the clinical staging of bladder tumors, particularly usual urothelial carcinomas, but possibly other histologic variants as well. A precedent for this approach was seen in recent TNM staging criteria used for testicular germ cell neoplasia, in which the presence of vascular invasion in an organ-confined tumor is classified as pT2 rather than pT1 disease. Similarly, patients with pT1-4, N0 bladder cancer could be upstaged accordingly.

We have much to explore before considering this hypothesis. As the authors state, the importance of lymphovascular invasion in predicting recurrence and survival in bladder cancer is controversial, in part because of the difficulty in determining its presence at the morphologic level. This fact is well documented in the literature in virtually every organ system. For example, in an article published in this journal by the Testicular Cancer Intergroup Study, the authors found that the recognition of vascular invasion differed significantly between local pathologists and central pathology review.² More importantly, vascular invasion as determined by central pathology review was a better predictor of relapse in both stage I and II disease.

Similar problems have been reported in bladder cancer. Larsen et al³ published their experience using Ulex europaeus agglutinin to confirm the presence of vascular invasion in T1 urothelial carcinoma. Of the 36 patients reported to have vascular invasion, this marker was able to confirm its presence in only five patients. The authors correctly emphasized the fact that retraction artifact, which mimics vascular invasion, is commonly seen in invasive urothelial carcinoma. In an article reviewing pathologic prognostic factors in bladder biopsy, transurethral resection, and cystectomy specimens, Lapham et al⁴ echo this remark and wisely advise that the presence of lymphovascular invasion should be reported only in unequivocal cases, and that—in some instances—it may require ancillary studies such as immunohistochemistry. Additional validation of lymphovascular invasion as a truly independent marker on which therapeutic decisions will be made is warranted. In addition, pathologists should strive to standardize criteria for establishing the presence of vascular invasion to diminish the problem of interobserver variability.

Another issue worthy of discussion is the advisability of using a pathology report as a research document. Despite the fact that this article deals with the clinical value of a morphologic finding, remarkably, not a single pathologist is included among its authors. The argument that the three participating institutions are academic centers with high volumes of urologic cancers seems a bit naïve, given that criteria for determining vascular invasion have certainly changed during the span of this study. Furthermore, the urologic cases at these institutions are evaluated not by dedicated urologic pathologists, but rather by pathologists with differing areas of interest and experience. In addressing this issue, the authors state, "the set-up of this study reflects a real-world practice in which multiple pathologists review tissue specimens and their interpretation is used in clinical decision making with the patient." Although this statement is certainly true, one must wonder whether one should base world-class research on real-world practice. I think not: lymphovascular invasion is not yet a tool for clinical decision making. Rather, it is a focus for prospective validation.

Author's Disclosures of Potential Conflicts of Interest

The author indicated no potential conflicts of interest.

REFERENCES

1. Lotan Y, Gupta A, Shariot S, 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 23:6533-6539, 2005[Abstract/Free Full Text]

2. Sesterhenn IA, Weiss RB, Mostofi FK, et al: Prognosis and other clinical correlates of pathologic review in stage I and II testicular carcinoma: A report from the Testicular Cancer Intergroup Study. J Clin Oncol 10:69-78, 1992[Medline]

3. 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 3:83-88, 1990[Medline]

4. Lapham RL, Grignon D, Ro JY: Pathologic prognostic parameters in bladder urothelial biopsy, transurethral resection, and cystectomy specimens. Semin Diagn Pathol 14:109-122, 1997[Medline]

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