According to the WHO classification of tumors of the urothelial tract, urothelial tumors include several variants: Infiltrating urothelial carcinomas with divergent differentiation, nested, microcystic, micropapillary, lymphoepithelioma-like, diffuse/plasmacytoid/signet ring cell, sarcomatoid, giant Cell, undifferentiated, lipid-rich, and clear cell.
VH is underrecognized, according to a study published in 2013.1 Out of 589 TURBTs, 19.5% had VH with 90% having one VH. According to this report, several types of VH were unrecognized. One of the problems of VH is that there is significant discordance among pathologists, with 93% agreement on classic forms, but a much lower agreement percentage reported for less common forms.
There is also some data showing that TURBT might not sufficiently show the presence of VH, even though it will eventually show up in radical cystectomy specimens of the same patients. It is not clear if this is because of tumor heterogeneity, or small samples taken in the TURBTs, not large enough to show the presence of VH.
Dr. Comperat then delved deeper into some of the specific VHs. She began discussing the subtype of micropapillary carcinoma. In a study analyzing cT1N0M0 micropapillary carcinoma patients, those who were treated with upfront radical cystectomy had a disease-specific survival of 100%, while those who were first treated with Bacillus Calmette–Guérin (BCG) had a recurrence in 75% of cases, and 45% of them had disease progression.2 Additionally, those treated with delayed radical cystectomy had a disease-specific survival of 62%, so the timing of therapy is also crucial. (2) Early identification of this specific variant and referring these patients to radical cystectomy as soon as possible saves lives.
Next, squamous cell carcinoma (SCC) variant was discussed. It is important to differentiate between pure SCC and SCC inflection. A study has shown that these two do not differ in cancer-specific and overall survival rates.3 It has been shown that cancer-specific and overall survival is worse in SCC if there are positive surgical margins. Additionally, positive lymph nodes confer worse overall and cancer-specific survival rates for SCC.
The plasmacytoid variant was discussed next. Small studies have shown these variants to have a two-fold increased risk of death (p=0.04). The treatment entails radical cystectomy and adjuvant cisplatin-based chemotherapy. It has a male to female ratio of 2:1 and is associated with high-grade urothelial carcinoma or sarcomatoid carcinoma. It is a diffusely spreading tumor, most commonly invading adjacent organs, and the clinical outcome is overall poor, with overall survival of 23 months.4
A recent publication assessed the role of trimodal therapy for the treatment of VHs. Overall 303 patients were analyzed, with 22% having VH. A total of 76% has SCC/glandular, and 24% had others. The study demonstrated a complete response rate of 82% in the VH patients compared to 83% in the non-variant group. The 5-year disease-specific survival for the VH group was 64%, and for the non-variant group, it was 75%5, demonstrating that VH does not influence outcomes significantly.
Unfortunately, there is only limited data on VH in non-muscle invasive bladder cancer (NMIBC). It is known that there are molecular differences between low grade and high-grade disease. NMIBC cells have basal and luminal-like characteristics with different outcomes. Understanding the molecular basis of NIMBC and muscle-invasive bladder cancer will help us understand different heterogenous groups within NMIBC, and perhaps enable us to know to whom to administer BCG. Dr. Comperat briefly discussed the molecular characterization of muscle-invasive bladder cancer as well.6 This characterization has a significant impact on the opportunity for immunological therapy, as it enables us to understand which cancer might respond well to immune therapy (Figure 1).
Figure 1 – Molecular characterization of muscle-invasive bladder cancer:
Summarizing her talk, Dr. Comperat stated that it is critically important to recognize VH and report it, as the implication on the therapy choices and outcomes are tremendous. Unfortunately, these are still under-recognized and underreported tumors, and there is a large discordance rate between pathologists on VH diagnosis. Furthermore, tumor heterogeneity is still a significant problem that needs to be dealt with. Hopefully, in the near future, incorporating molecular data could help us treat these patients appropriately.
Presented by: Eva Comperat, MD, Head of the Department of Pathology at the L'Assistance Publique-Hôpitaux de Paris, Hôpital Tenon, in Paris, France
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre @GoldbergHanan at the Global Conference on Bladder Cancer 2018 - September 20-21, 2018 Madrid, Spain
References:
1. Shah RB, et al. Urologic oncology 2013; 31(8): 1650-5.
2. Willis DL, et al. J Urol 2015; 193(4): 1129-34.
3. Ehdaie et al. J Urol 2012
4. Zuckenberg et al. 1991 AM J Surg Pathol
5. Krasnow et al. Eur Urol 2016
6. Robertson AG et al. Cell 2018; 174(4): 1033.