CUA 2018: Update on Variant Histologies in Urothelial Carcinoma

Halifax, Nova Scotia ( At the 2018 Canadian Urological Oncology Group multidisciplinary meeting, CUA 2018, Dr. van der Kwast from Toronto provided the pathologist’s perspective regarding variant histology and urothelial carcinoma. Dr. van der Kwast started by noting 2016 WHO definitions for variant urothelial histology, including:

  • Nested/microcystic
  • Micropapillary
  • Lymphoepithelioma-like
  • Plasmacytoid
  • Sarcomatoid
  • Poorly differentiated
The variant non-urothelial histologies include pure squamous cell carcinoma, adenocarcinoma, or neuroendocrine carcinoma. 

Dr. van der Kwast notes that one of the most important pathological questions is what distinguishes pure squamous cell carcinoma from urothelial carcinoma from urothelial carcinoma with squamous differentiation? The consensus among pathologists is that: the presence of any urothelial carcinoma component and/or urothelial carcinoma in situ would preclude a diagnosis of pure squamous cell carcinoma. Wide surgical resection is critical to achieve local tumor control and improve survival in patients with pure squamous cell carcinoma. Patients with urothelial carcinoma with squamous and/or glandular differentiation are more likely to have pT3-pT4 tumors (70% vs 38%, p<0.0001) and pN+ disease (20% vs 15%, p=0.05) compared to those with purely urothelial carcinoma1. The major issues with squamous differentiation of several-fold:

  • There is no consistent reporting by pathologists
  • There is no established cut-off for the proportion of squamous differentiation
  • Quantification is difficult, but now recommended by WHO as of 2016
  • For pure squamous cell carcinoma at TUR, there is discordance at the time of radical cystectomy
It is important to note that primary adenocarcinoma of the bladder needs to be differentiated from invasion from adjacent organs or distant metastases. Neuroendocrine carcinoma is one of the most aggressive histologies and frequently pT3 and N+, whereas squamous cell carcinoma is less frequently pN+ but more frequently pT3 at cystectomy. Adenocarcinoma has the same outcome and pN+ status characteristics as pure urothelial carcinoma but is more often pT3 at the time of cystectomy.

The nested variant was first described in 1979 and is an unusual bladder tumor of Brunn nest origin. The male to female ratio of this tumor is 4:1, with a mean age of presentation of 65 years of age. Often, it is associated with high-grade urothelial carcinoma, although it has no specific gross findings and is found in association with CIS and papillary tumors. In a study of nested variant vs urothelial carcinoma at the T1 stage, there was no difference in metastasis-free survival (p=0.2) and cancer-specific survival (p=0.2) compared to patients with pure urothelial carcinoma2. However, patients with T1 nested variant had a 54% (vs 14% in the urothelial cohort) rate of upstaging at cystectomy, including 31% with node-positive (vs 0% in the urothelial cohort) disease.

The micropapillary variant is associated with varying sizes of tumor nests and multiple nests within the same lacunar space. Single institutional studies, such as those from MD Anderson Cancer Center, have noted that those with the pure cT1 micropapillary disease should undergo immediate cystectomy; the extent of the micropapillary component has been shown to influence BCG-responsiveness3.

Plasmacytoid urothelial carcinoma has to be differentiated from lymphoma, signet ring cell carcinoma and metastases from other sites such as the stomach and breast. Plasmacytoid is often associated with high-grade urothelial carcinoma and sarcomatoid differentiation, and the prognosis is directly related to the stage of the disease. The clinical outcome is uniformly poor, with an overall survival median of 23 months, secondary to diffuse spreading to adjacent organs. Unique to the plasmacytoid variant, it has been described as spreading rapidly along fascial planes.

Dr. van der Kwast concluded with several take-home messages/diagnostic and therapeutic challenges:

  • There is underreporting and interobserver variation with regards to variant histologies
  • Upstaging is frequent
  • There is often a discrepancy between the TUR specimen and pathology at the time of cystectomy
  • Stage adjusted survival is worse only for neuroendocrine and plasmacytoid variant and probably for pure squamous cell carcinoma.
1. Kim SP, Frank I, Cheville JC, et al. The impact of squamous and glandular differentiation on survival after radical cystectomy for urothelial carcinoma. J Urol 2012;188(2):405-409.
2. Mally AD, Tin AL, Lee JK, et al. Clinical outcomes of patients with T1 nested variant of urothelial carcinoma compared to pure urothelial carcinoma of the bladder. Clin Genitourin Cancer 2017 July 14 [Epub ahead of print].
3. Willis DL, Fernandez MI, Dickstein RJ, et al. Clinical outcomes of cT1 micropapillary bladder cancer. J Urol 2015;193(4):1129-1134.

Presented by: Theo van der Kwast, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre Twitter: @zklaassen_md at the 73rd Canadian Urological Association Annual Meeting - June 23 - 26, 2018 - Halifax, Nova Scotia

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