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. 2021 May 26;13(11):2615.
doi: 10.3390/cancers13112615.

Intravesical Bacillus Calmette-Guérin Treatment for T1 High-Grade Non-Muscle Invasive Bladder Cancer with Divergent Differentiation or Variant Morphologies

Makito Miyake  1 , Nobutaka Nishimura  1 , Kota Iida  1 , Tomomi Fujii  2 , Ryoma Nishikawa  3 , Shogo Teraoka  3 , Atsushi Takenaka  3 , Hiroshi Kikuchi  4 , Takashige Abe  4 , Nobuo Shinohara  4 , Eijiro Okajima  5 , Takuto Shimizu  6 , Shunta Hori  1   6 , Norihiko Tsuchiya  7 , Takuya Owari  1 , Yasukiyo Murakami  8 , Rikiya Taoka  9 , Takashi Kobayashi  10 , Takahiro Kojima  11 , Naotaka Nishiyama  12 , Hiroshi Kitamura  12 , Hiroyuki Nishiyama  11 , Kiyohide Fujimoto  1
Affiliations

Intravesical Bacillus Calmette-Guérin Treatment for T1 High-Grade Non-Muscle Invasive Bladder Cancer with Divergent Differentiation or Variant Morphologies

Makito Miyake et al. Cancers (Basel). .

Abstract

The 2016 World Health Organization classification newly described infiltrating urothelial carcinoma (UC) with divergent differentiation (DD) or variant morphologies (VMs). Data comparing oncological outcomes after bladder-preservation therapy using intravesical Bacillus Calmette-Guérin (BCG) treatment among T1 bladder pure UC (pUC), UC with DD (UC-DD), and UC with VMs (UC-VM) are limited. We evaluated 1490 patients with T1 high-grade bladder UC who received intravesical BCG during 2000-2019. They were classified into three groups: 93.6% with pUC, 4.4% with UC-DD, and 2.0% with UC-VM. Recurrence-free, progression-free, and cancer-specific survival following intravesical BCG were compared among the groups using multivariate Cox regression analysis, also used to estimate inverse probability of treatment weighting-adjusted hazard ratio and 95% confidence interval for the outcomes. Glandular differentiation and micropapillary variant were the most common forms in the UC-DD and UC-VM groups, respectively. Of 1490 patients, 31% and 13% experienced recurrence and progression, respectively, and 5.0% died of bladder cancer. Survival analyses revealed the impact of concomitant VMs was significant for cancer-specific survival, but not recurrence-free and progression-free survival compared with that of pUC. Our analysis clearly demonstrated that concomitant VMs were associated with aggressive behavior in contrast to concomitant DD in patients treated with intravesical BCG.

Keywords: Bacillus Calmette–Guérin (BCG); divergent differentiation; immunotherapy; survival; urinary bladder neoplasms; variant morphology.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow chart for creation of the patient cohort dataset. From the original dataset, the cohort was restricted to T1 high-grade urothelial carcinoma (UC). Abbreviations: NMIBC, non-muscle invasive bladder cancer; BCG, Bacillus Calmette–Guérin; pUC, pure urothelial carcinoma; DD, divergent differentiation; VM, variant morphology; IPTW, inverse probability of treatment weighting.
Figure 2
Figure 2
Divergent differentiation and variant morphologies in T1 high-grade urothelial carcinoma of cases from this study. All the illustrative images of hematoxylin-eosin staining were captured at original magnification 200×. (A) Squamous differentiation; (B) Glandular differentiation. This tumor has enteric features and mucin production; (C) Nested variant; (D) Micropapillary variant; (E) Sarcomatoid variant; (F) Clear cell variant; (G) Microcystic variant. This tumor forms neoplastic cystic structure. The lumina tend to be empty, but some of them contain necrotic cells, granular eosinophilic debris, or mucin (arrowheads); (H) Giant cell variant. This tumor has pleomorphic giant cells (black arrows) with cytoplasmic vacuoles.
Figure 3
Figure 3
Survival curves of outcomes after initiation of intravesical BCG treatment among pure UC, UC with DD, and UC-VMs. Bladder recurrence-free survival (A), progression-free survival (B), and cancer-specific survival (C) were plotted and compared among three groups. Abbreviations: BCG, Bacillus Calmette–Guérin; UC, urothelial carcinoma; DD, divergent differentiation; VM, variant morphology.
See this image and copyright information in PMC

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