A 2-center review of histopathology of variants of upper urinary tract urothelial carcinoma and their impact on clinical outcomes.

INTRODUCTION: Similar to bladder cancer, about one third of upper tract urothelial carcinoma (UTUC) present variant histology (VH). We aim to evaluate the incidence, clinical characteristics and the impact on outcomes of VH in UTUC. METHODS: We consecutively enrolled 77 patients treated between 2009 and 2022 by radical surgery for UTUC from a secondary and a tertiary referral center. A pathology review of all specimens was performed by 1 independent uropathologist for each center. We compared pure UTUC and UTUC with VH and the accuracy of endoscopic biopsy. Descriptive and comparative analysis was performed to assess the association with clinical characteristics and the Kaplan-Meier estimator to compare outcomes. RESULTS: Median follow-up after surgery was 51 months. VH was present in 21/77 (28%) patients and 4/21 (19%) patients had multiple variants. The most frequent VH was squamous 12/21 (57%), followed by glandular 7/21 (33%) and micropapillary 3/21 variants (14%). Neuroendocrine carcinoma was present in 2 patients. Nested variant was found in 1 patient. Muscle invasive tumor (≥pT2) was present in 30/56 (54%) patients with pure UTUC and in 18/21 (86%) patients with VH (P < 0.05). Presence of carcinoma in situ was seen in 24/56 (43%) patients with pure UTUC and in 16/21 (76%) with VH (P < 0.05). Cumulative 8/56 (14%) with pure UTUC had a nonintravesical recurrence (6 patients with local and 2 distant recurrence) compared to 8/21 (38%) (3 local, 3 nodal, 2 distant) in the subgroup with VH (P < 0.05). Opposite effect was noted for bladder recurrence: 60% for pure UTUC vs. 29% for tumors with VH (P < 0.05). Review of preoperative endoscopic biopsy did not show the presence of VH in any patients. Differences in outcomes did not reach significance: 3yr-OS 63% vs. 42% (P 0.28) and 3yr-CSS 77% vs. 50% (P 0.7). CONCLUSION: Almost a third of UTUC present VH. Presence of VH is related to more aggressive tumor characteristics and associated with unfavorable outcomes. Due to a higher rate of extravesical recurrences in UTUC with VH, Follow-up controls should include cross sectional imaging and cystoscopy.

MUC1 is upregulated in advanced prostate cancer and is an independent prognostic factor.

BACKGROUND: MUC1 is a membrane-bound glycoprotein that belongs to the mucin family. It is involved in cell adhesion and intracellular signaling. Aberrant expression of MUC1 has been observed in different carcinomas, including prostate cancer, where it may serve as a therapeutic target. There are no data on the prognostic value of MUC1 in metastatic prostate cancer. METHODS: MUC1 expression was evaluated in tissue microarrays constructed from 119 nodal positive prostate cancer patients treated by radical prostatectomy and extended lymphadenectomy. MUC1 status was correlated with various tumor features and biochemical recurrence-free (bRFS), disease-specific survival (DSS) and overall survival (OS). RESULTS: MUC1 expression was significantly different between primary tumors, lymph node metastases and non-neoplastic glands (scores 53.7 vs 30.1 vs 16.6; P<0.0001). High MUC1 expression in primary tumors was positively correlated with tumor volume (mean 24.4 cm(3) vs 14.5 cm(3); P=0.005) and T-stage (P=0.009); in lymph node metastases, high expression corresponded with a greater total size of metastases (mean 35.8 mm vs 12.7 mm; P<0.001) and a higher ratio of positive to examined lymph nodes (mean 0.22 vs 0.12; P=0.014). High MUC1 expression in lymph node metastases predicted unfavorable outcomes compared with low MUC1 expression (bRFS P=0.023, DSS and OS P⩽0.001), whereas in primary tumors, the same tendency was non-significant. In multivariate analyses, high MUC1 expression in primary tumors and lymph node metastases independently predicted early biochemical failure (P=0.046) and tumor-related death (P=0.0038), respectively. CONCLUSIONS: High MUC1 in either primary tumor or lymph node metastases correlates significantly with unfavorable tumor features and survival. Overexpression of MUC1 in the metastases of a subset of prostate cancer patients may have therapeutic potential.

CD4 T cells are required for both development and maintenance of disease in a new mouse model of reversible colitis.

Current therapies to treat inflammatory bowel diseases have limited efficacy, significant side effects, and often wane over time. Little is known about the cellular and molecular mechanisms operative in the process of mucosal healing from colitis. To study such events, we developed a new model of reversible colitis in which adoptive transfer of CD4(+)CD45RB(hi) T cells into Helicobacter typhlonius-colonized lymphopenic mice resulted in a rapid onset of colonic inflammation that was reversible through depletion of colitogenic T cells. Remission was associated with an improved clinical and histopathological score, reduced immune cell infiltration to the intestinal mucosa, altered intestinal gene expression profiles, regeneration of the colonic mucus layer, and the restoration of epithelial barrier integrity. Notably, colitogenic T cells were not only critical for induction of colitis but also for maintenance of disease. Depletion of colitogenic T cells resulted in a rapid drop in tumor necrosis factor α (TNFα) levels associated with reduced infiltration of inflammatory immune cells to sites of inflammation. Although neutralization of TNFα prevented the onset of colitis, anti-TNFα treatment of mice with established disease failed to resolve colonic inflammation. Collectively, this new model of reversible colitis provides an important research tool to study the dynamics of mucosal healing in chronic intestinal remitting-relapsing disorders.

Morphological and molecular characteristics of HER2 amplified urothelial bladder cancer.

Several (pre-) clinical trials are currently investigating the benefit of HER2-targeted therapy in urothelial bladder cancer (UBC). Patients with HER2 amplified UBC could potentially profit from these therapies. However, little is known about histomorphology, HER2 protein expression patterns and occurrence of alterations in the HER2 gene in their tumors. Among 150 metastasizing primary UBC, 13 HER2 amplified tumors were identified. Their histopathological features were compared with 13 matched, non-amplified UBC. HER2 protein expression was determined by immunohistochemistry. The 26 tumors were screened for mutations in exons 19 and 20 of the HER2 gene. UBC with HER2 amplification presented with a broad variety of histological variants (median 2 vs. 1), frequently featured micropapillary tumor components (77 % vs. 8 %) and demonstrated a high amount of tumor associated inflammation. Immunohistochemically, 10 of 13 (77 %) HER2 amplified tumors were strongly HER2 protein positive. Three tumors (23 %) were scored as HER2 negative. One of the HER2 amplified tumors harbored a D769N mutation in exon 19 of the HER2 gene; all other tested tumors were wild type. In conclusion, HER2 amplified UBC feature specific morphological characteristics. They frequently express the HER2 protein diffusely and are, therefore, promising candidates for HER2 targeted therapies. The detection of mutations at the HER2 locus might add new aspects to molecular testing of UBC.