Bladder diverticula are herniations of bladder urothelium and mucosa through the muscularis propria. The reported incidence of neoplasia arising in bladder diverticula is widely variable. The ...authors' objective was to study the characteristics and sensitivity of urine cytology in these patients with emphasis on primary intradiverticular bladder cancer (IDBC).
A 17-year, retrospective review of all resected bladder diverticula associated with bladder carcinoma was performed. Cases that had complete diverticular resections and preresection urine samples were included in this study. The cases were divided into either primary IDBC or primary extradiverticular bladder cancer (EDBC). Demographic data and urine cytology characteristics were recorded, and sensitivity was calculated. For IDBC, a comparison between voided and cystoscopic urines was done for cases that had both collection methods performed.
Of 70 patients with IDBC, 47 patients had urine cytology results that were either positive for high grade-urothelial carcinoma (HG-UC) or suspicious for HG-UC. The sensitivity for HG-UC in IDBC samples was 80%, compared with 82% in EDBC samples (p > .05). Also, 28 patients in the IDBC group had both voided and cystoscopic urine samples for comparisons; in seven patients, the voided urine sample yielded a more definitive diagnosis; in 10 patients, the cystoscopic urine sample yielded a more definitive diagnosis; and, in 11 patients, both samples were equally diagnostic (p > .05).
The characteristics and sensitivity of urine cytology in bladder diverticula were investigated in association with neoplasia, with an emphasis on primary intradiverticular bladder cancer. The results indicated that urine cytology remains a reliable screening and diagnostic test for detecting IDBC, with sensitivity similar to that for detecting EDBC, and no significant difference was noted between voided and cystoscopic samples.
Histological and molecular analyses of urothelial carcinoma often reveal intratumoural and intertumoural heterogeneity at the genomic, transcriptional and cellular levels. Despite the clonal ...initiation of the tumour, progression and metastasis often arise from subclones that can develop naturally or during therapy, resulting in molecular alterations with a heterogeneous distribution. Variant histologies in tumour tissues that have developed distinct morphological characteristics divergent from urothelial carcinoma are extreme examples of tumour heterogeneity. Ultimately, heterogeneity contributes to drug resistance and relapse after therapy, resulting in poor survival outcomes. Mutation profile differences between patients with muscle-invasive and metastatic urothelial cancer (interpatient heterogeneity) probably contribute to variability in response to chemotherapy and immunotherapy as first-line treatments. Heterogeneity can occur on multiple levels and averaging or normalizing these alterations is crucial for clinical trial and drug design to enable appropriate therapeutic targeting. Identification of the extent of heterogeneity might shape the choice of monotherapy or additional combination treatments to target different drivers and genetic events. Identification of the lethal tumour cell clones is required to improve survival of patients with urothelial carcinoma.
CD8
T cell reactivity towards tumor mutation-derived neoantigens is widely believed to facilitate the antitumor immunity induced by immune checkpoint blockade (ICB). Here we show that broadening in ...the number of neoantigen-reactive CD8
T cell (NART) populations between pre-treatment to 3-weeks post-treatment distinguishes patients with controlled disease compared to patients with progressive disease in metastatic urothelial carcinoma (mUC) treated with PD-L1-blockade. The longitudinal analysis of peripheral CD8
T cell recognition of patient-specific neopeptide libraries consisting of DNA barcode-labelled pMHC multimers in a cohort of 24 patients from the clinical trial NCT02108652 also shows that peripheral NARTs derived from patients with disease control are characterised by a PD1
Ki67
effector phenotype and increased CD39 levels compared to bystander bulk- and virus-antigen reactive CD8
T cells. The study provides insights into NART characteristics following ICB and suggests that early-stage NART expansion and activation are associated with response to ICB in patients with mUC.
Small-cell carcinoma of the bladder (SCCB) is a rare and aggressive neuroendocrine tumor with a dismal prognosis and limited treatment options. As SCCB is histologically indistinguishable from ...small-cell lung cancer, a shared pathogenesis and cell of origin has been proposed. The aim of this study is to determine whether SCCBs arise from a preexisting urothelial carcinoma or share a molecular pathogenesis in common with small-cell lung cancer.
We performed an integrative analysis of 61 SCCB tumors to identify histology- and organ-specific similarities and differences.
SCCB has a high somatic mutational burden driven predominantly by an APOBEC-mediated mutational process.
, and
promoter mutations were present in nearly all samples. Although these events appeared to arise early in all affected tumors and likely reflect an evolutionary branch point that may have driven small-cell lineage differentiation, they were unlikely the founding transforming event, as they were often preceded by diverse and less common driver mutations, many of which are common in bladder urothelial cancers, but not small-cell lung tumors. Most patient tumors (72%) also underwent genome doubling (GD). Although arising at different chronologic points in the evolution of the disease, GD was often preceded by biallelic mutations in
with retention of two intact copies.
Our findings indicate that small-cell cancers of the bladder and lung have a convergent but distinct pathogenesis, with SCCBs arising from a cell of origin shared with urothelial bladder cancer.
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Mutations, deletions, and changes in copy number of mitochondrial DNA (mtDNA), are observed throughout cancers. Here, we survey mtDNA copy number variation across 22 tumor types profiled by The ...Cancer Genome Atlas project. We observe a tendency for some cancers, especially of the bladder, breast, and kidney, to be depleted of mtDNA, relative to matched normal tissue. Analysis of genetic context reveals an association between incidence of several somatic alterations, including IDH1 mutations in gliomas, and mtDNA content. In some but not all cancer types, mtDNA content is correlated with the expression of respiratory genes, and anti-correlated to the expression of immune response and cell-cycle genes. In tandem with immunohistochemical evidence, we find that some tumors may compensate for mtDNA depletion to sustain levels of respiratory proteins. Our results highlight the extent of mtDNA copy number variation in tumors and point to related therapeutic opportunities.
Aim
Clinicopathologic characterisation of a contemporary series of neuroendocrine (NE) differentiation in the setting of prostatic carcinoma (PCa) was examined.
Methods and results
We reviewed ...institutional databases for in‐house cases with a history of PCa and histopathologic evidence of NE differentiation during the disease course. In all, 79 cases were identified: 32 primary and 47 metastases. Metastatic lesions were in liver (n = 15), lymph node (n = 9), bone (n = 6), lung (n = 3), brain (n = 1), and other sites (n = 13). In all, 63 of 76 (82%) cases with NE differentiation and available history were posttherapy: six postradiation therapy (RT), 24 post‐ androgen–deprivation therapy (ADT), and 33 post‐RT + ADT. Morphologic assessment (n = 79): (i) 23 pure small‐cell/high‐grade NE carcinoma (HGNEC): 20/23 metastatic; (ii) 10 combined high‐grade PCa and small‐cell/HGNEC: 9/10 primary; (iii) 15 PCa with diffuse NE immunohistochemistry (IHC) marker positivity/differentiation, associated with nested to sheet‐like growth of cells with abundant cytoplasm and prominent nucleoli, yet diffuse positivity for at least one prostatic and one NE IHC marker: all metastatic; (iv) 11 PCa with patchy NE differentiation, displaying more than single‐cell positivity for NE IHC: five primary / six metastatic; (v) nine PCa with focal NE marker positive cells: four primary / five metastatic; (vi) 11 PCa with ‘Paneth cell‐like’ change: all primary.
Conclusions
In this contemporary series, the majority of NE differentiation in the setting of PCa was seen posttherapy. We highlight the tendencies of small‐cell/HGNEC and PCa with diffuse NE differentiation by IHC to occur in metastatic settings, while morphologically combined high‐grade PCa + small‐cell/HGNEC and ‘Paneth cell‐like’ change occur in primary disease.
Incidence, setting (primary v. metastatic), and therapeutic history of various neuroendocrine manifestations in the setting of prostatic carcinoma.
Objective
To evaluate whether urothelial carcinoma (UC) with sarcomatoid differentiation is associated with a lower pathological response rate to neoadjuvant chemotherapy (NAC) and worse oncological ...outcomes compared to UC without variant histology among patients undergoing radical cystectomy.
Patients and Methods
Patients with UC undergoing cystectomy from 1995 to 2018 at the Memorial Sloan Kettering Cancer Centre were identified. Patients with sarcomatoid differentiation at transurethral resection (TUR) or cystectomy, and patients without variant histology were selected. Downstaging from ≥cT2 to ≤pT1N0 defined partial response and pT0N0 defined complete response. Recurrence‐free, cancer‐specific and overall survival were modelled.
Results
We identified 131 patients with sarcomatoid differentiation and 1722 patients without variant histology, of whom 25 with sarcomatoid histology on biopsy and 313 without variant histology received NAC. Those with sarcomatoid differentiation presented with higher consensus tumour stage (94% ≥T2 vs 62%; P < 0.001) and were, therefore, more likely to receive NAC (29% vs 18%; P = 0.003). We found no evidence to support a difference in partial (24% vs 31%) or complete (20% vs 24%) response between patients with sarcomatoid histology and those with pure UC at TUR (P = 0.6). Among patients with sarcomatoid differentiation, 5‐year recurrence‐free survival was 55% (95% confidence interval CI 41–74) among patients receiving NAC and 40% (95% CI 31–52) among patients undergoing cystectomy alone (P = 0.1). Adjusting for stage, nodal involvement, margin status and receipt of NAC, sarcomatoid differentiation was associated with worse recurrence‐free (hazard ratio HR 1.82, 95% CI 1.39–2.39), disease‐specific (HR 1.66, 95% CI 1.23–2.22), and overall survival (HR 1.37, 95% CI 1.06–1.78).
Conclusions
Sarcomatoid differentiation was associated with higher stage at presentation and independently associated with worse survival. Given similar pathological response rates if sarcomatoid differentiation is detected at initial resection, and greater survival among patients receiving NAC, treatment with NAC appears warranted. Other drivers of the poor outcomes of this histology must be investigated.
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