Survival Impact of Variant Histology Diagnosis in UTUC

Upper tract urothelial carcinoma (UTUC) is a rare disease, contributing only 10% of all cases of urothelial carcinoma in the United States.¹ However, findings with improved imaging and endoscopic technologies reveal that the incidence of UTUC appears to be rising.² Although UTUC is often considered similar to bladder cancer, there are embryologic differences in the development of the bladder compared with the upper tract and genetic differences in their respective oncologic molecular profiles. UTUC appears to have less frequent mutations of RB1 and TP53, and more frequently present with mutations in FGFR3.

Additionally, there is a significant familial relationship between UTUC and deficiencies in mismatch repair genes that contribute to Lynch syndrome (LS), with UTUC associated with LS in up to 10% of all UTUC cases.³ However, the genomic profile of UTUC is not the most clinically significant parameter for patients with this disease. Tumor stage and grade remain the most significant prognostic factors in cases of UTUC.⁴ Notably, up to one-third of all patients with UTUC present with variant histology, usually with nonstandard differentiation, such as squamous or micropapillary features.

Significance of UTUC Histologies

Less frequently, pure nonurothelial upper tract disease occurs. These variant histologies have been found to be associated with worse oncologic outcomes in patients with bladder cancer,⁵ but have not been evaluated in those with upper tract disease. Instead, the clinical significance of variant histology in upper tract disease has been derived secondhand from our management of bladder cancer, given their histologic similarities.

However, the diagnostic pathways by which bladder cancer and UTUC are managed differ greatly, given the technical challenges present with obtaining appropriate staging for UTUC. In upper tract disease, it is often achievable to establish tumor grade via biopsy but difficult to appropriately stage the depth of invasion of the tumor.⁶ It is critical to better understand the impact of variant histology in UTUC on patient outcomes to appropriately tailor the approach to management. For these reasons, Nogueira et al evaluated the survival impact of variant histologies in patients with upper tract disease at their institution and recently published their findings in the Journal of Urology.⁷

The authors reviewed 23 years of consecutive patients who underwent nephroureterectomy for upper tract disease at Memorial Sloan Kettering Cancer Center, finding >700 unique patients. Surgical approach and choice to perform lymph node dissection were at the surgeon’s discretion. All patients were offered standardized follow-up postoperative regimens and were monitored for disease recurrence (defined as any disease relapse).

Variant histology was identified in the specimens of 47 patients (6.7%). Squamous differentiation was found in 28 of these patients’ specimens; sarcomatoid differentiation was found in 8; glandular differentiation was found in 3 specimens, 2 of which had pure squamous cell carcinoma; and 1 specimen had several other variants. Notably, the prevalence of variant histology significantly increased over time. Patients with variant histology were significantly more likely to have received neoadjuvant chemotherapy prior to their definitive nephroureterectomy, but they were still found to have higher T-staging on final pathology than patients with nonvariant histology.

Reviewing Patients With Variant Histology

Importantly, variant histology was found to be associated with a significantly increased risk of worse cancer-specific survival (CSS; hazard ratio [HR], 2.14) as well as overall survival (OS; HR, 1.74). However, there was no significant association found between recurrence-free survival (RFS) and variant histology. The authors then adjusted for T-staging and found no association of variant histology with any difference in survival outcomes. They also found similar results when evaluating for survival outcomes after disease recurrence. Univariate analysis revealed that variant histology was associated with worse CSS and OS after recurrence. However, when the authors performed multivariable analysis, they found that the CSS differences were likely explained by higher pathologic T-staging, whereas the association with OS remained present.

The data and analysis presented by Nogueira et al provide a large retrospective review of patients with nephroureterectomy, ~6.5% of whom had variant histology in their final pathologic specimens. Variant histology was associated with higher stage and greater likelihood of having received neoadjuvant chemotherapy before definitive surgical extirpation. Moreover, variant histology was associated with worse CSS and OS, but no worse RFS after nephroureterectomy. Notably, once the authors controlled for pathologic staging, there were no significant survival differences seen in patients with a variant histology. In other words, perceived worse survival associated with variant histology is likely to be related to worse pathologic T-staging, with individuals who have variant histology also happening to be more likely to have higher staging.

Multiple prior studies have shown consistent results, with univariate analysis showing survival differences in patients variant histology but loss of this significance, when results are controlled for staging. The authors point out that this finding is also demonstrated in the bladder cancer setting, where variant histology is often diagnosed at a higher stage and greater burden of disease, but analyses demonstrate that stage-matched survival is often similar to that in patients with typical urothelial carcinoma.

As the authors note, their cohort comprised only patients who underwent nephroureterectomy. There may be an inherent selection bias present, as these patients typically are selected because of their advanced disease stage or tumor grade. Smaller or low-grade tumors are often treated with endoscopic management in the effort to ensure renal preservation, and thus would be excluded from the cohort the authors analyzed.

What does this mean for the prognostic significance of variant histology in UTUC? Based on the findings by Nogueira et al, it seems variant histology may be a useful predictor of higher risk disease although it does not add predictive postsurgical prognostic value. The authors note that this is what their data imply, but they are quick to point out that their study was not designed to evaluate such a hypothesis, and such a conclusion cannot be made definitively. Despite the limitations of this study, the presence of UTUC variant histology remains a useful biomarker.

Daniel Tennenbaum is a urology resident at Maimonides Medical Center in Brooklyn, NY. His interests include surgical education and GU oncology with a focus on pediatric malignancies.

References

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3. Audenet F, Isharwal S, Cha EK et al. Clonal relatedness and mutational differences between upper tract and bladder urothelial carcinoma. Clin Cancer Res. 2019;25(3):967- 976. doi: 10.1158/1078-0432.CCR-18-2039.
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5. Lobo N, Shariat SF, Guo CC, et al. What is the significance of variant histology in urothelial carcinoma? Eur Urol Focus. 2020;6(4):653-663. doi: 10.1016/j.euf.2019.09.003.
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7. Nogueira LM, Yip W, Assel MJ, et al. Survival impact of variant histology diagnosis in upper tract urothelial carcinoma. J Urol. 2022;208(4):813-820. doi: 10.1097/ JU.0000000000002799