We aimed at assessing the impact of non-urothelial variant histology (VH), relative to urothelial carcinoma of the urinary bladder (UCUB), on cancer-specific mortality (CSM) in T2N0M0 bladder cancer patients treated with trimodal therapy (TMT). TMT patients treated for T2N0M0 bladder cancer were identified within the Surveillance, Epidemiology, and End Results database (2000−2018). Patients who underwent TMT received trans-urethral resection of the bladder tumor, chemotherapy, and radiotherapy. CSM-FS rates were tested using Kaplan−Meier plots and multivariable Cox-regression (MCR) models according to histological subtype: UCUB vs. neuroendocrine carcinoma vs. squamous cell carcinoma vs. adenocarcinoma. A total of 3846 T2N0MO bladder cancer patients treated with TMT were identified. Of these, 3627 (94.3%) harbored UCUB, while 105 (2.7%), 85 (2.2%), and 29 (0.8%) harbored neuroendocrine carcinoma, squamous cell carcinoma, and adenocarcinoma, respectively. In Kaplan−Meier analyses, 3-yr CSM-FS rates were 57% for UCUB, 51% for neuroendocrine carcinoma, 35% for squamous cell carcinoma, and 60% for adenocarcinoma (p-value < 0.0001). In MCR models, only squamous cell carcinoma exhibited higher CSM than UCUB (HR 1.98, 95%CI 1.5−2.61, p-value < 0.001). Despite the small number of observations, squamous cell carcinoma distinguished itself from UCUB based on worse survival in T2N0M0 patients after TMT.

To assess the effect of event-free survival duration on cancer-specific mortality (CSM) after radical cystectomy (RC) in nonmetastatic muscle-invasive squamous cell carcinoma of the urinary bladder.
RC patients treated for non-metastatic muscle-invasive squamous cell carcinoma of the urinary bladder were identified within the Surveillance, Epidemiology, and End Results database (2000-2018). Independent predictor status for CSM of T and N stage groupings (i.e., T2N0, T3N0, T4N0, and TanyN1-3) was tested in multivariable Cox-regression models. Conditional 5-year CSM-free estimates were assessed at baseline and at 4 specific event-free survival times (i.e. 6, 12, 18 and 24 months), within each of the 4 examined stage groups.
Of 981 RC patients, 206 (21%), 416 (42%), 152 (16%), and 207 (21%) were T2N0, T3N0, T4N0, and TanyN1-3, respectively. In multivariable Cox-regression models T3N0 (HR 1.94), T4N0 (HR 5.22), and TanyN1-3 (HR 6.62) were independent predictors of CSM, relative to T2N0. In conditional survival analyses based on 24 months event-free status, survival estimates were: 89% for T2N0 vs. 76% at baseline (Δ = 13%), 84% for T3N0 vs. 58% at baseline (Δ = 26%), 69% for T4N0 vs. 25% at baseline (Δ = 44%), 69% for TanyN1-3 vs. 22% at baseline (Δ = 47%).
Event-free status at 24 months of follow-up is associated with substantially higher CSM-free survival than when CSM-free survival is predicted at baseline. The magnitude of this effect is most pronounced in TanyN1-3 and T4N0 patients, intermediate in T3N0 and more modest, nonetheless important, in T2N0.

The analysis of the tumor microenvironment, especially tumor-infiltrated immune cells, is essential for predicting tumor prognosis, clinical outcomes, and therapy strategies. Adrenocortical cancer is a rare nonimmunogenic malignancy in which the importance of the presence of immune cells is not well understood. In our study, we made the first attempt to understand the interplay between the histology of adrenocortical cancer and its immune landscape using cases from The Cancer Genome Atlas database and the Endocrinology Research Centre collection (Moscow, Russia). We showed that the oncocytic variant of adrenocortical cancer is characterized by intensive immune infiltration and better survival, and it is crucial to analyze the effect of immune infiltration independently for each histological variant.

BACKGROUND: The efficacy of anti-programmed celldeath protein 1 treatment in patients with urothelial carcinoma (UC) with molecular subtypes of histological variants has not been investigated. This study aimed to examine the impact of histological variants classified according to molecular subtypes on clinical outcomes in patients with platinum-resistant metastatic UC treated with pembrolizumab.
METHODS: Data of 168 patients with metastatic UC who received intravenous pembrolizumab after platinum-based chemotherapy between December 2017 and November 2020 were retrospectively reviewed. Relationships between histological variant type (basal or luminal molecular subtypes) and survival outcome and response to immunotherapy were examined. Clinicopathological factors were analyzed using the Cox proportional hazards model.
RESULTS: UC with histological variants was identified in 19 (11.3%) cases (basal subtype in 12; luminal subtype in 7). The median age of the patients was 72.5 years (range=40-89 years). The performance status was 0-1 in 151 (89.9%) patients. Liver metastasis was detected in 44 (26.2%) patients. The median progression-free survival was 3.5 months (range=0.5-34.3 months). Treatment with immune checkpoint inhibitors resulted in an overall mean survival (from the start of treatment) of 8.1 months (range=1.2-34.3 months). Patients with basal-type UC had significantly shorter progression-free survival and cancer-specific survival than those with pure UC (p=0.010 and p=0.035, respectively). A complete response was observed in eight patients (seven with pure UC, one with basal type).
CONCLUSIONS: The basal histological variant might be a potential prognostic indicator in patients with platinum-resistant metastatic UC treated with pembrolizumab.

Although variant urothelial carcinoma (VUC, defined here as urothelial carcinoma with any histological variant) is a clinically aggressive disease, the efficacy of pembrolizumab against VUC is not well characterized. This study assessed the therapeutic response and survival outcomes in patients with advanced VUC treated with pembrolizumab for unresectable recurrent or metastatic disease.
We retrospectively evaluated 103 patients with advanced bladder and upper urinary tract cancer who received pembrolizumab after failure of platinum-based chemotherapy at 6 institutions between January 2018 and June 2021. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were compared between patients with pure urothelial carcinoma (PUC) and those with VUC.
We identified 81 and 22 patients with PUC and VUC, respectively. Squamous differentiation (n = 14) was the most common variant element, followed by glandular differentiation (n = 3) and micropapillary variant (n = 3). Baseline characteristics were comparable between the groups. Patients with VUC showed significantly better ORR (59.1% vs. 29.6%, P = .014) and comparable DCR (68.2% vs. 49.4%, P = .150) compared to those with PUC. There were no significant differences between the PUC and VUC groups with respect to PFS (median 5.0 months vs. 10.4 months, P = .222) or OS (median 13.5 months vs. 23.8 months, P = .497).
Response of VUC to pembrolizumab was not inferior to that of PUC in patients with advanced-stage bladder and upper urinary tract cancer.

Papillary thyroid carcinoma (PTC) is a miscellaneous disease with a variety of histological variants, each with its own mutational profile, and clinical and prognostic characteristics. Identification of microRNA (miRNA) expression profiles represents an important benchmark for understanding the molecular mechanisms underlying the biological behavior of these unique PTC subtypes in order that they be better characterized. We considered a series of 35 PTC samples with a histological diagnosis of either hobnail (17 cases) or classical variant (nine cases) and with a specific BRAF p.K601E mutation (nine cases). We determined the overall miRNA expression profile with NanoString technology, and both quantitative reverse transcription-PCR and in situ hybridization were used to confirm selected miRNAs. The miRNA signature was found to consistently differentiate specific histotypes and mutational profiles. In contrast to the BRAF p.K601E mutation and classic PTCs, three miRNAs (miR-21-5p, miR-146b-5p, and miR-205-5p) were substantially overexpressed in the hobnail variant. The current study found that different miRNA signature profiles were linked to unique histological variants and BRAF mutations in PTC. Further studies focusing on the downstream pathogenetic functions of mRNAs in thyroid neoplasms are warranted.

Basal/squamous (Ba/Sq) subtype represents an intrinsic and robust group in the consensus molecular classification of muscle-invasive bladder cancer (MIBC), with poor outcome and controversial chemosensitivity. We aimed to investigate the spectrum of intratumor heterogeneity (ITH) in the Ba/Sq subtype. First, we validated a 29-gene NanoString CodeSet to predict the Ba/Sq subtype for FFPE samples. We identified heterogeneous Ba/Sq tumors in a series of 331 MIBC FFPE samples using dual GATA3/KRT5/6 immunohistochemistry (IHC). Heterogeneous regions with distinct immunostaining patterns were studied separately for gene expression using the 29-gene CodeSet, for mutations by targeted next-generation sequencing, and for copy number alteration (CNA) by microarray hybridization. Among 83 Ba/Sq tumors identified by GATA3/KRT5/6 dual staining, 19 tumors showed heterogeneity at the IHC level. In one third of the 19 cases, regions from the same tumor were classified in different distinct molecular subtypes. The mutational and CNA profiles confirmed the same clonal origin for IHC heterogeneous regions with possible subclonal evolution. Overall, two patterns of intratumoral heterogeneity (ITH) were observed in Ba/Sq tumors: low ITH (regions with distinct immunostaining, but common molecular subtype and shared CNA) or high ITH (regions with distinct immunostaining, molecular subtype, and CNA). These results showed multilayer heterogeneity in Ba/Sq MIBC. In view of personalized medicine, this heterogeneity adds complexity and should be taken into account for sampling procedures used for diagnosis and treatment choice. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

OBJECTIVE: To assess the impact of histological variants on survival and response to treatment with pembrolizumab in patients with chemo-resistant urothelial carcinoma (UC).
METHODS: The medical records of 755 patients with advanced UC who received pembrolizumab were reviewed retrospectively. Patients were classified into pure UC (PUC) and each variant. Best overall response (BOR) and overall survival (OS) were compared between the groups using a propensity score matching (PSM).
RESULTS: Overall, 147 (19.5%) patients harboured any histological variant UC (VUC). After PSM, there were no significant differences in the objective response rate (ORR, 24.5% vs 17.3%, P = 0.098) or disease control rate (DCR, 36.7% vs 30.2%, P = 0.195) when comparing patients with any VUC and PUC. Furthermore, any VUC, as compared with PUC, was associated with a similar risk of death (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.68-1.20; P = 0.482). Squamous VUC, which was the most frequent variant in the cohort, had a comparable ORR, DCR and OS as compared with PUC or non-squamous VUC. The patients with sarcomatoid VUC (n = 19) had significantly better ORR (36.8%, P = 0.031), DCR (52.6%, P = 0.032), and OS (HR 0.37, 95% CI 0.15-0.90; P = 0.023) compared to patients with PUC.
CONCLUSIONS: The presence of variant histology did not seem to affect BOR or OS after pembrolizumab administration in patients with chemo-resistant UC. The patients with sarcomatoid VUC achieved favourable responses and survival rates compared to PUC.

Pure invasive papillary carcinoma (IPC) is a rare subtype of breast carcinoma with good prognosis compared with classical invasive breast carcinoma (IBC) of no special type. The majority of IPC are estrogen receptor and progesterone receptor (ER/PR) positive and HER2 negative (luminal A-like). We report the case of a 72-year-old women who was referred to the Senology Clinic for a routine workup following surgery for an intraductal papilloma. The core needle biopsy (CNB) showed a lesion mainly composed of irregular papillae and micropapillae with apocrine epithelial cells of low-to-intermediate nuclear grade, without a myoepithelial cell layer within the papillae and at the periphery, as demonstrated with multiple immunostains. The diagnosis of apocrine papillary lesion of uncertain malignant potential was made. The subsequent lumpectomy showed an IBC with the same cyto-architectural features as the CNB. In addition, lymphovascular invasion and papillary/micropapillary apocrine in situ lesion were noted. Notably, the tumor was ER/PR and HER2 negative and strongly positive for androgen receptor. A final diagnosis of mixed apocrine papillary/micropapillary carcinoma with triple-negative status was made. To the best of our knowledge, this is the first report of an IBC with these features. Breast pathologists should be aware of this entity when dealing with CNB samples characterized by a complex papillary lesion with apocrine atypia that lacks a myoepithelial cell layer on multiple immunostains. These lesions should be classified at least as of uncertain malignant potential based on the cyto-architectural features prompting a surgery for removal.

OBJECTIVE: Bladder cancer with histological variant (HV) has different morphological features from usual urothelial carcinoma (UC). The aim of this study was to evaluate the oncological outcomes of HV in patients with bladder cancer.
METHODS: We retrospectively evaluated data from 102 patients with UC of the bladder treated with radical cystectomy between 1998 and 2017. Pathological findings including HV were assigned by one dedicated pathologist. Recurrence-free survival (RFS) and cancer-specific survival (CSS) and overall survival (OS) were estimated by Cox regression models.
RESULTS: In total, 26 patients (25.5%) had HV, and the most common variant was squamous differentiation, followed by glandular differentiation and a mixed variant consisted of squamous and glandular differentiation. The presence of HV was associated with RFS and CSS (p=0.018, p=0.036, respectively).
CONCLUSIONS: HV has more aggressive tumor biological features compared to those with pure UC. The presence of HV was associated with poor survival.