The effects of clinicopathological and imaging findings on recurrence and survival in mammary Paget's disease.

OBJECTIVE: Mammary Paget's disease (MPD) is a rare presentation type of breast cancer. The aim of this study was to evaluate the clinicopathological and imaging features affecting the invasive component, loco-regional recurrence, prognosis, and survival of MPD. METHODS: Patients who had undergone surgery due to MPD in a 10-year period were included. Parameters including mammography and magnetic resonance imaging (MRI) findings, tumor stage, molecular subtype, axillary involvement, presence of invasive carcinoma, loco-regional recurrence, overall survival (OS), and disease-free survival (DFS) were recorded and statistically analyzed. P<0.05 was determined as statistically significant. RESULTS: The study group consisted of 49 women with a mean age of 67.05±14.43 (range: 23-90) years. There was a significant association between the presence of invasive carcinoma and a mass lesion in the MRI (p=0.002). The frequency of sentinel lymph node (SLN) metastasis was significantly higher in patients with multicentric tumors (p=0.029; p<0.05). Locoregional recurrence and distant metastasis were significantly more frequent in patients with axillary involvement (p=0.0336; p<0.05). The mean DFS was 115.02±7.28 months, while the mean OS was 119.29±6.57 months. CONCLUSION: The presence of a mass lesion on MRI was determined to be significant in recognizing invasive carcinoma in MPD. The rate of SLN metastasis was higher in patients with multicentric tumors than in patients with unifocal tumors. Axillary involvement was associated with impaired DFS.

The Impact of Histological Variants on Oncological Outcomes in Patients with Muscle Invasive Bladder Cancer Treated with Radical Cystectomy.

OBJECTIVE: Bladder cancer is a heterogeneous entity characterized by a wide range of different morphologies. The aim of this study was to investigate the prognostic effect of bladder tumor with variant histology that is treated with radical cystectomy on oncological outcomes. METHODS: One hundred eighty-six patients who underwent radical cystectomy between September 2001 and June 2020 were included in the study. The patients were divided into 2 groups variant histology group (n = 54) and transitional cell cancer group (n = 132). Clinicopathologic data were compared between the two groups. RESULTS: The groups were similar in terms of demographic characteristics. In the mul- tivariate analysis of cancer-specific survival in transitional cell cancer against variant histology, high-grade detection of primary transurethral bladder tumor pathology, cystectomy pT, cystectomy positive lymph node, and positive surgical margin in cys- tectomy were determined to be statistically significant. Diagnosis of pT2 and high grade of primary transurethral bladder tumor pathology, cystectomy ≥ pT3, cystec- tomy positive lymph node, and positive surgical margin in cystectomy were statis- tically significant in multivariate analysis of overall survival. Cancer-specific survival time was estimated at 65.1 ± 8.3 months for variant histology and 134.2 ± 10.4 months for transitional cell cancer (P=.004). The estimated overall survival time was 61.9 ± 8.0 months in variant histology and 119.0 ± 9.8 months in transitional cell cancer (P = .014). CONCLUSION: Pathological features and prognosis of bladder cancer with variant histol- ogies are worse than those of pure urothelial bladder cancer. Overall survival and can- cer-specific survival are shorter in bladder cancer with variant histology than in pure urothelial bladder cancer. Following the diagnosis of variant histology in transurethral bladder tumor, poor prognosis must be considered in the treatment plan.

Clinicopathologic features and prognostic significance of mixed (Low and high-grade) papillary urothelial carcinoma comparison with low and high-grade papillary urothelial carcinoma.

The World Health Organization/International Society of Urological Pathology (2022 WHO/ISUP) classification categorizes noninvasive carcinomas based on the highest grade observed in a pathology sample. According to this classification, a lesion is classified as mixed-grade (MG) if the highest-grade component comprises less than 5% high-grade (HG) carcinoma [14]. This study included 160 cases of low-grade papillary urothelial carcinoma (LGUC) and 160 cases of HG papillary urothelial carcinoma (HGUC), selected randomly. In addition, 160 consecutive and unselected cases of MG papillary urothelial carcinoma (MGUC) were obtained from all bladder transurethral resection specimens diagnosed with papillary urothelial carcinoma between January 2007 and January 2021. The results of the multivariate analysis showed that histologic grade, invasion of the lamina propria, and the presence of carcinoma in situ at presentation were independent prognostic parameters regarding recurrence-free survival (p = 0.002; hazard ratio (HR) = 1.44, 95% confidence interval (CI) = 1.059-1.956, p = 0.02; and HR = 1.76, 95% CI = 1.159-2.684, p = 0.008, respectively). Histologic grade was the only independent prognostic parameter of disease-specific survival (DSS) (p < 0.001). Comparisons between non-muscle invasive (NMI) MGUC and NMI LGUC, as well as between NMI MGUC and NMI HGUC, revealed statistically significant differences in terms of DSS (HR = 0.07, 95% CI = 0.024-0.252, p < 0.001 and HR = 1.59, 95% CI = 1.023-2.460, p = 0.039, respectively). Our study findings demonstrate statistically significant differences regarding DSS between NMI MGUC and NMI HGUC, as well as between NMI MGUC and NMI LGUC. Therefore, we suggested that considering the presence of less than 5% MGUC as a separate category may be appropriate. However, it is important to validate our results in larger cohorts with longer follow-up periods to establish the clinical significance of MGUC and provide guidance for patient management.

Histopathologic Follow-Up of Women with Inadequate ThinPrep™ Cervical Pap Tests and Positive High-Risk Human Papillomavirus Test Results.

INTRODUCTION: We found only a few studies that had performed high-risk human papillomavirus (hrHPV) analyses of inadequate ThinPrep™ Papanicolaou (Pap) tests. Therefore, this study aimed to analyze unsatisfactory ThinPrep Pap tests using hrHPV tests. The colposcopic biopsy results of cases with an unsatisfactory ThinPrep Pap test and positive hrHPV results were revealed. METHODS: Between January 1, 2018, and October 31, 2022, 965 (3.7%) of 25,958 liquid-based cytology specimens were evaluated as unsatisfactory. Ninety-five (9.8%) of 965 patients were positive for hrHPV. The colposcopic evaluation was performed in 28 (29.4%) of 95 patients, in whom 23 tests were adequate. RESULTS: Twenty-three colposcopy biopsy results showed that 17 (73.9%) of 23 patients had benign biopsy results. High-grade squamous intraepithelial lesions were observed in three (13%) of the 23 patients, and low-grade squamous intraepithelial lesions were observed in two (8.6%) of the 23 patients. One of the 23 (4.3%) patients had keratinized squamous cell carcinoma of the cervix diagnosed histologically, although no tumor was visible upon gynecologic examination. CONCLUSION: For the management of unsatisfactory Pap tests, The American Society for Colposcopy and Cervical Pathology (ASCCP) recommends repeat cytology within 2-4 months. Evaluation of such patients using hrHPV tests may triage those with squamous intraepithelial lesions, even invasive cervical cancer. More studies with a larger number of cases are needed to analyze the hrHPV status and biopsy follow-up of cases with unsatisfactory cytology.

Immediate histopathologic correlation in Turkish population with negative cytology and high-risk human papillomavirus positivity: A retrospective analysis of high-risk human papillomavirus genotype and stratified by age.

INTRODUCTION: According to the American Society of Colposcopy and Cervical Pathology (ASCCP) recommendations, regardless of age, women with high-risk infections other than human papillomavirus 16/18 positivity (other hrHPV) and negative cytology should not be referred directly to colposcopy. Several studies compared detection rates of ≥high-grade squamous intraepithelial lesion (HSIL) between HPV 16/18 ± 45, and other hrHPV types on colposcopic biopsy. METHODS: We designed a retrospective study to determine the presence of ≥HSIL in colposcopic biopsy in women with negative cytology and hrHPV positivity during the years 2016-2022. RESULTS: HPV 16/18/45 had a PPV of 43.8%, while other hrHPV types had a PPV of 29.1% for a tissue diagnosis of ≥HSIL. For a tissue diagnosis of ≥HSIL detection, there was no statistically significant difference between the PPV of other hrHPV and HPV 16/18/45 in patients ≥30. There were only two cases with a tissue diagnosis of ≥HSIL in the other hrHPV group of women under 30 years of age. CONCLUSION: We suggested that the follow-up recommendations of ASCCP for patients above the age of 30 with negative cytology and other hrHPV positivity may not be fully applicable to countries like Turkey with a different healthcare environment. Referring to patients ≥30 who had other hrHPV positivity and negative cytology to direct colposcopy may be clinically beneficial, particularly in populations where a colposcopic examination is easy and inexpensive.

Comparison of the Clinical Performance of Aptima HPV Assay and the Cobas 4800 Platform in Women with Normal Cytology and Positive High-Risk HPV.

INTRODUCTION: According to the current American Society for Colposcopy and Cervical Pathology (ASCCP) guidelines, patients with normal cytology results may be referred for colposcopy according to their high-risk human papillomavirus (hrHPV) test results. A higher positive predictive value (PPV) of hrHPV has significance for preventing unnecessary colposcopic examinations. Several studies have compared the performance of the Aptima assay and the Cobas 4800 platform among patients who had minor cytologic abnormalities. However, in our English literature search, we found no other study that had been conducted to compare these two methods in patients with normal cytology. We thus aimed to compare the PPV of the Aptima assay and the Cobas 4800 platform among women with normal cytology. METHODS: Between September 2017 and October 2022, we retrospectively identified 2,919 patients who had normal cytology and hrHPV positivity and had been referred for a colposcopy. Among them, 882 agreed to undergo a colposcopy; on examination, 134 had target lesions revealed and underwent a colposcopic punch biopsy. RESULTS: Among the patients who underwent a colposcopic punch biopsy, 49 (38.9%) were tested with Aptima, and 77 (61.1%) were tested with Cobas. In the Aptima group, 29 (59.2%) patients showed benign histology, 2 (4.1%) patients had low-grade squamous intraepithelial lesions (LSILs), and 18 (36.7%) patients had ≥high-grade squamous intraepithelial lesions (HSILs) biopsy results. The false-positivity rate and PPV of Aptima were 63.3% (31/49) and 36.7% (95% confidence interval [CI]: 0.232-0.502), respectively, for a histopathologic diagnosis of ≥HSIL. In the Cobas group, 48 (62.3%) biopsies were benign, 11 (14.3%) reported an LSIL, and 18 (23.4%) biopsies were ≥HSIL. The false-positivity rate and PPV of Cobas were 76.6% (59/77) and 23.4% (95% CI: 0.139-0.328), respectively, concerning a ≥HSIL tissue diagnosis. The false-positivity rate of Aptima HPV 16 positivity was 40% (4/10). The false-positivity rate of Cobas HPV 16 positivity was 61.1% (11/18). The PPVs of HPV 16 positivity for Aptima and Cobas were 60% (95% CI: 0.296-0.903) and 38.9% (95% CI: 0.163-0.614), respectively, concerning ≥HSIL tissue diagnosis. CONCLUSION: We recommend analyzing the performances of hrHPV platforms in future, larger studies in patients with normal cytology rather than only in cases with abnormal cytology.

The cribriform morphology impairs Gleason 7 prostate cancer lesion detection on multiparametric magnetic resonance imaging.

BACKGROUND: Prostate multiparametric magnetic resonance imaging (mpMRI) is a useful tool for the detection of tumor lesions however, some clinically significant lesions are still missed. We determined whether the cribriform pattern has an effect on lesion detection in mpMRI. METHODS: We reviewed the single-institution database of the patients who underwent mpMRI before radical prostatectomy. We included the patients only with the Gleason 7 final pathology of open radical prostatectomy with curative intent between 2016 and 2021. Prostatectomy mappings according to the 16-sector map and cribriform patterns were re-evaluated by two genitourinary pathologists. Prostate mpMRIs were read by two genitourinary radiologists. If the index and nonindex lesions in pathology mapping were matched with mpMRI as Prostate Imaging Reporting and Data System-3 or higher, it was defined as detectable. We compared the detection rates of lesions with and without cribriform morphology. In regression analysis, we also assessed the factors affecting the detectability of prostate cancer lesions. RESULTS: A total of 120 patients and 157 lesions were included in our study. While 52 of 83 cribriform pattern positive lesions could be detected in mpMRI, 59 of 74 cribriform pattern negative lesions could be detected (62.7% vs. 79.7%, respectively, p = 0.019). The lesions were also distributed homogeneously according to diameters and analyzed separately. All lesions between 21 and 30 mm with the negative cribriform pattern were detected on mpMRI. However, only 77.8% of cribriform pattern positive lesions between 21 and 30 mm could be detected (p = 0.034). The Higher D'Amico risk group and the absence of cribriform morphology were independent predictors for the lesion detection on mpMRI. CONCLUSION: The presence of cribriform pattern in Gleason 7 prostate cancer lesions decreases the lesion detection rate of mpMRI.

High-risk human papillomavirus (HPV) detection in formalin-fixed paraffin-embedded cervical tissues: performances of Aptima HPV assay and Beckton Dickinson (BD) Onclarity assay.

AIM: There are many scenarios where high-risk human papillomavirus (HPV) detection in formalin-fixed paraffin-embedded (FFPE) specimens is important. However, there is no Food and Drug Administration (FDA)-approved and clinically validated technique for detecting high-risk HPV in FFPE tissues. In this study, we evaluated two commercially available HPV assays which are FDA-approved for use on cytology specimens, the Aptima HPV assay and the Beckton Dickinson (BD) Onclarity assay, to detect high-risk HPV in FFPE tissues of cervical high-grade squamous intraepithelial lesion (HSIL) and squamous cell carcinoma (SCC). METHODS: A total of 189 cases (46 SCC, 107 HSIL and 36 benign/normal) were tested for high-risk HPV with the Aptima HPV assay and a subset of cases (n=97) with the BD Onclarity assay. RESULTS: The sensitivities of the Aptima and BD Onclarity HPV assays were 99.4% (95% CI 96.46% to 99.98%) and 75.9% (95% CI 65.27% to 84.62%), respectively; the specificity and positive predictive value (PPV) of the two assays were 100%. Negative predictive values of the Aptima and BD Onclarity HPV assays were 97.3% (95% CI 83.61% to 99.61%) and 67.7% (95% CI 58.91% to 75.47%), respectively. The kappa value (0.96) for comparison of the distribution of high-risk HPV types between the two assays was high. HPV 16 was the most common high-risk HPV type for HSIL and SCC cases. However, SCC cases had higher percentages of HPV 16 and HPV 18/45 and lower percentages of other high-risk HPV types compared with HSIL cases. CONCLUSION: Both assays are reliable methods for high-risk HPV detection and genotype determination in FFPE specimens, with high PPV and specificity. The Aptima HPV assay has the advantage of higher sensitivity. As far as we are aware, this is the first study comparing the Aptima HPV assay and the BD Onclarity assay in FFPE tissues. Our study results should be tested and confirmed in larger cohorts.

The prognostic impact of tumor necrosis in non-muscle invasive bladder cancer.

OBJECTIVE: We aimed to investigate the impact of tumor necrosis in non-muscle invasive bladder cancer on patients' recurrence and progression rates and survival outcomes. METHODS: This study was conducted retrospectively in a single tertiary center in Turkey. Medical records of patients who underwent transurethral resection of the bladder tumor between January 2016 and January 2021 were reviewed. Patients with pTa and pT1 non-muscle invasive bladder cancer who had undergone complete resection were included in our study. All pathological specimens were reevaluated for the presence of tumor necrosis. RESULTS: A total of 287 patients (244 males and 43 females) were included in our study. Of them, 33 (11.5%) patients had tumor necrosis. The rates of multiple and large tumors (>3 cm) were higher in patients with tumor necrosis (p=0.002 and p<0.001, respectively). Tumor necrosis was associated with higher rates of pT1 diseases (p<0.001), high-grade tumors (p<0.001), and the presence of lymphovascular invasion (p=0.007). The mean recurrence-free survival of patients with tumor necrosis was 42.3 (4.6) months, and the recurrence-free survival of patients without tumor necrosis was 43.5 (1.8) months (p=0.720). The mean progression-free survival of patients with tumor necrosis was 43.1 (4.6) months, and the progression-free survival of patients without tumor necrosis was 58.4 (0.9) months. In log-rank analysis, there was a statistically significant difference between patients with and without tumor necrosis in terms of progression-free survival (p<0.001). CONCLUSION: In this study, we demonstrated that patients with non-muscle invasive bladder cancer and tumor necrosis in pathological specimens have shorter progression-free survival and more adverse pathological features.

The prognostic impact of tumor necrosis in non-muscle invasive bladder cancer

SUMMARY OBJECTIVE: We aimed to investigate the impact of tumor necrosis in non-muscle invasive bladder cancer on patients' recurrence and progression rates and survival outcomes. METHODS: This study was conducted retrospectively in a single tertiary center in Turkey. Medical records of patients who underwent transurethral resection of the bladder tumor between January 2016 and January 2021 were reviewed. Patients with pTa and pT1 non-muscle invasive bladder cancer who had undergone complete resection were included in our study. All pathological specimens were reevaluated for the presence of tumor necrosis. RESULTS: A total of 287 patients (244 males and 43 females) were included in our study. Of them, 33 (11.5%) patients had tumor necrosis. The rates of multiple and large tumors (>3 cm) were higher in patients with tumor necrosis (p=0.002 and p<0.001, respectively). Tumor necrosis was associated with higher rates of pT1 diseases (p<0.001), high-grade tumors (p<0.001), and the presence of lymphovascular invasion (p=0.007). The mean recurrence-free survival of patients with tumor necrosis was 42.3 (4.6) months, and the recurrence-free survival of patients without tumor necrosis was 43.5 (1.8) months (p=0.720). The mean progression-free survival of patients with tumor necrosis was 43.1 (4.6) months, and the progression-free survival of patients without tumor necrosis was 58.4 (0.9) months. In log-rank analysis, there was a statistically significant difference between patients with and without tumor necrosis in terms of progression-free survival (p<0.001). CONCLUSION: In this study, we demonstrated that patients with non-muscle invasive bladder cancer and tumor necrosis in pathological specimens have shorter progression-free survival and more adverse pathological features.

Comparison of 68Ga-PSMA PET/CT and mp-MRI in regard to local staging for prostate cancer with histopathological results: A retrospective study.

BACKGROUND: Imaging modalities are used to diagnose and clinical grading of clinically significant prostate cancer. In this study, 68Ga-PSMA PET/CT (PSMA) and multiparametric prostate MRI (mp-MRI) were compared in regard to locating intraprostatic tumor and locoregional staging. METHODS: After ethics committee approval, a total of 49 patients with prostate cancer who had mp-MRI and PSMA before radical prostatectomy were included. Preoperative and postoperative PSA, transrectal ultrasound-guided prostate biopsy (TRUS-Bx) ISUP grade, radical prostatectomy ISUP grade, body mass index (BMI), TRUS prostate volume, mp-MRI tumor mapping, PSMAtumor mapping, pathologic tumor mapping, extraprostatic extension (EPE), seminal vesicle invasion (SVI), lymph node invasion (LNI), and bladder neck invasion (BNI)were retrospectively evaluated. Index tumor was located by uroradiologist, nuclear medicine specialist, and uropathologist on a 12-sector prostate pathology map and compared with each other in terms of accuracy and locoregional clinical staging. RESULTS: Mean age of the patients was 66.18 ± 6.67 years and the mean of preoperative PSA results was 21.11 ± 32.56 ng/ml. Nearly half of the patients' (44.9%) pathology was reported as ISUP grade 4 and 5% and 18.4% of patients were surgical margin positive. According to the pathological findings, 362 out of 588 sectors were tumor-positive, 174 out of 362 sectors were tumor-positive in mp-MRI, and 175 out of 362 sectors were tumor-positive in PSMA. Both PSMA and mp-MRI were comparable (p = 0.823) and accurate to detect the location of the intraprostatic index tumor (AUC = 0.66 vs. 0.69 respectively, p = 0.82). The sensitivity and the specificity of the PSMA and mp-MRI for localizing intraprostatic index tumors were 42.5% versus 49.5% and 90.7% versus 88.6% respectively. mp-MRI was more accurate than PSMA in terms of EPE (AUC = 0.8 vs. AUC = 0.57 respectively, p = 0.027) and both methods were comparable in terms of SVI (AUC = 0.75 vs. AUC = 0.75, p = 0.886) and BNI (AUC = 0.51 vs. AUC = 0.59, p = 0.597). PSMA and mp-MRI were comparable in terms of LNI (AUC = 0.76 vs. AUC = 0.64, p = 0.39). CONCLUSION: mp-MRI should be considered for its high accuracy in the diagnosis of EPE, especially before decision-making for nerve-sparing surgery in high-risk patients. Both imaging modalities were accurate for localizing intraprostatic index tumor. PSMA is accurate for detecting LNI.

The association between PI3K, JAK/STAT pathways with the PDL-1 expression in prostate cancer.

Programmed cell death protein-1/programmed death-ligand-1 (PD-1/PDL-1) signalling pathway has gained attention in prostate cancer. The relationship between pSTAT-1, pSTAT-3 expressions and PTEN loss with PDL-1 expression was assessed and the effects of the pathways on prostate cancer prognosis were evaluated. Patients who underwent radical prostatectomy between 2011 and 2017 were included in our study. Prostatectomy materials were evaluated using immunohistochemical staining of pSTAT-1, pSTAT-3, PTEN, and PDL-1. The relationship between PDL-1 and pSTAT-1, pSTAT-3 expressions and PTEN loss was evaluated. Additionally, factors affecting biochemical recurrence-free survival and clinical progression-free survival were analysed. Within100 patients, 9 of 11 patients with PDL-1 expression also had intermediate-high pSTAT-1 staining intensity, and those with PDL-1 expression had higher pSTAT-1 staining intensity than those without (81.9% vs. 56.2%, p = 0.014). In univariate analysis, pSTAT-1, pSTAT-3 and PDL-1 expressions had significant impact on biochemical recurrence-free and clinical progression-free survival. In multivariate analysis, pSTAT-1 staining intensity with radical prostatectomy ISUP grade in terms of biochemical recurrence-free survival and the pSTAT-1 H-score with radical prostatectomy ISUP grade in terms of clinical progression-free survival were independent risk factors. Moderate-high expression of pSTAT-1 was closely associated with PDL-1 expression, and pSTAT-1 was also a predictor of biochemical recurrence and clinical progression.

Relation of beclin-1 and bcl-2 expressions with pathological parameters and prognosis in clear cell renal cell carcinomas.

INTRODUCTION: The most common type of renal cancers is the clear cell renal cell carcinoma (CCRCC) and 98% of CCRCCs have a loss of sequence in the short arm of chromosome 3 by deletion or translocation. Programmed cell death; another possible mechanism of tumorigenesis, comprises two separate components: apoptosis and autophagy. This study aims to show the rela-tion between the prognostic parameters and survival, and Beclin-1, as the representative marker of autophagy, and Bcl-2 as the representative marker of apoptosis in CCRCC patients. In this study, we aimed to determine if Beclin-1 and Bcl-2 expression levels can provide any prognostic information about CCRCC patients. METHODS: We examined a total of 84 patients who underwent partial or radical nephrectomy and were diagnosed as having CCRCC between January 2008 and December 2015. Immunohistochemical staining was performed, the evaluation was for Beclin-1 and Bcl-2 semi-quantitative, and based on the percentage of positively stained cells (proportion) and staining intensity. RESULTS: There was only a statistical significance between Beclin-1 expression and age (r:-0.274; p=0.012; p <0.05). There was a marginal significance between ISUP grade and Beclin-1 (p=0.051). The relation of Bcl-2 expression with the ISUP grade, recurrence, metastasis, and mortality revealed statistical significance (p=0.001, p=0.019, p=0.009, p=0.013, respectively). The ISUP grade and the Bcl-2 expression revealed statistical significance on multivariate analysis ( HR 7.453, 95% CI: 1.935-28.713, p=0.004). The 5-year and 10-year tumor recurrences rates were lower in Bcl-2 positive group, and Bcl-2 positive group experi-enced longer disease free and overall survival. CONCLUSION: There was only marginal correlation between Beclin-1 expression and ISUP grade. No other histopathologic prog-nostic parameters histologic parameters revealed any signigificance. The higher expression of Bcl-2 is correlated with nuclear lower ISUP grade, lower pT stage, and longer disease free and overall survival.

PTEN Loss and PD-L1 Expression of Different Histological Patterns of Prostate Cancer.

AIMS: Although several studies have evaluated PTEN loss in Prostatic Adenocarcinoma (PCa), PTEN loss correlation with different histological patterns only has a few studies. Although several studies have evaluated PD-L1 expression in PCa and its correlation with Gleason scores, as far as we know, there are no prior studies that have included a comparison between PD-L1 expression and histological patterns of PCa. This study aims to evaluate PTEN loss and PD-L1 expression by immunohistochemistry in different histological patterns of PCa. METHODS: The current study included consecutive 98 radical prostatectomy specimens with 151 foci with different Gleason Grade (GG) patterns. RESULTS: The highest frequency of PTEN loss was observed in GG4 cribriform and glomeruloid patterns (59.3%, p < 0.001). Combined score (CS) PD-L1 positivity was observed in fourteen patients (14.2%). Tumor cell (TC) and tumor-associated inflammatory cells (IC) PD-L1 positivity was observed in 10 (10.2%) and 7 (7.1%) patients. The highest frequency of PD-L1 expression was observed in the GG5 pattern, and between GG4 patterns, the irregular pattern had the highest PD-L1 positivity. CONCLUSIONS: In conclusion, in our cohort of consecutive unselected cases of prostatic carcinoma, we observed the highest PTEN loss rate in the GG4 cribriform and glomeruloid pattern and the highest PD-L1 expression rate in the GG5 and GG4 irregular patterns. These results may predict molecular differences between different histological patterns in PCa and may be used to inform a treatment decision. Future studies should investigate these differences between histological patterns of PCa to predict response to immunotherapy in larger cohorts.

The Correlation of Histopathologic Parameters With Mismatch Repair Protein-deficient Subgroups and MLH1 Methylation in Endometrial Carcinomas.

There are limited data regarding the correlation of clinical and pathologic parameters with mismatch repair (MMR) protein-deficient subgroups and methylation status. In this study, we analyzed the status of MMR proteins in resection specimens of 198 consecutive endometrial carcinomas and the methylation status in tumors with MLH1 and PMS2 deficiency. We, therefore, assessed the correlation of clinical and pathologic parameters with MMR protein-deficient subgroups. Univariate analysis revealed that deeper myometrial invasion and the presence of tumor-associated lymphocytes were more frequently observed in tumors with MMR protein deficiency ( P =0.023 and 0.001, respectively). The multivariate logistic regression analysis revealed that only the presence of tumor-associated lymphocytes was significantly associated with MMR protein deficiency ( P =0.002, odds ratio=2.674, 95% confidence interval=1.418-5.045). We also compared MLH1 and PMS2 deficiency with other protein deficiency regarding clinical and pathologic parameters. Furthermore, we compared MLH1 methylated tumors with MMR protein-deficient nonmethylated tumors regarding clinical and pathologic parameters. MLH1 was methylated in 51 of 54 tumors with MLH1 and PMS2 deficiency. In univariate analysis, a larger tumor size was significantly associated with MLH1 and PMS2 deficiency and with MLH1 methylation ( P =0.004 and 0.005, respectively). The multivariate logistic regression analysis revealed that a larger tumor size was significantly associated with MLH1 and PMS2 deficiency and MLH1 methylation ( P =0.002, odds ratio=14.222, 95% confidence interval=2.560-79.026, P =0.008, odds ratio=22.222, 95% confidence interval=2.220-222.395, respectively). Our results showed a slightly higher rate of MLH1 and PMS2 deficiency (34.3%) than in previous studies. This may likely be due to ethnic differences in frequency of various mutations.

The Clinical Impact of Tumor Grade Heterogeneity in Non-muscle-invasive Urothelial Carcinoma of the Bladder.

OBJECTIVE: This study aimed to determine the oncological outcomes of mixed-grade tumors by comparing them with pure low-grade and high-grade tumors. METHODS: We retrospectively reviewed the medical records of patients with primary non-muscle-invasive bladder cancer. Patients were categorized into three groups according to the histological grade of their tumors: low-grade, mixed-grade, and high-grade. Clinicopathological characteristics and oncological outcomes, such as recurrence-free survival (RFS), progression-free survival (PFS), and cancer-specific survival (CSS), were compared between the three groups. RESULTS: A total of 369 patients (190 low, 40 mixed, and 139 high-grade) were included in our study, with a mean follow-up of 55.94±41.73 months. Patients with mixed-grade tumors had lower rates of pT1 stage diseases than those with high-grade tumors (42.5% vs. 64.0%, respectively) and higher rates than those with low-grade tumors (14.7% vs. 42.5%, respectively) (p=0.001). There was no significant difference in RFS between low-, mixed-, and high-grade tumor patients (p=0.887). Patients with mixed-grade tumors had worse PFS and CSS outcomes than those with low-grade tumors (199.84±23.22 vs. 214.94±15.92 for PFS and 202.07±19.86 vs. 233.61±9.84 for CSS, respectively) and better PFS and CSS outcomes than those with high-grade tumors (199.84±23.22 vs. 163.28±16.18 for PFS and 202.07±19.86 vs. 180.81±15.89 for CSS, respectively), although these comparisons were not statistically significant. CONCLUSIONS: Patients with mixed-grade tumors had worse PFS and CSS outcomes than patients with low-grade tumors and better PFS and CSS outcomes than patients with high-grade tumors, although these comparisons were not statistically significant. Our results should be verified by future studies.

Hepatocellular adenomas in the Turkish population: reclassification according to updated World Health Organization criteria.

AIMS: Hepatocellular adenoma (HCA) is an uncommon liver neoplasm, and studies of HCA subtypes have been primarily limited to France, the USA, and Japan. The aim of this study was to describe the clinicopathological features of HCA subtypes in Turkey. METHODS AND RESULTS: The resection specimens of 59 cases diagnosed as 'hepatocellular adenoma' collected from 15 institutions were reviewed to confirm the diagnosis and to classify them according to the current World Health Organization 2019 classification. Immunostaining for glutamine synthetase, liver fatty acid-binding protein, C-reactive protein, ß-catenin and reticulin was performed. Of the 59 cases, 48 (81%) were diagnosed as HCA. We identified 24 (50%) hepatocyte nuclear factor 1α (HNF1α)-inactivated HCAs, five (10%) inflammatory HCAs, 15 (32%) ß-catenin-activated HCAs, three (6%) ß-catenin-activated inflammatory HCAs, and one (2%) unclassified HCA. HCA patients were predominantly female (female/male ratio of 5:1); they had a median age of 34 years and a median tumour diameter of 60 mm. In the ß-catenin-activated HCA group, nine cases (19%) showed cytoarchitectural atypia, and were also referred to as atypical hepatocellular neoplasms. In the ß-catenin-activated HCA group, three cases (6%) showed focal areas supportive of transition to HCA. The original diagnosis of HCA was changed to well-differentiated hepatocellular carcinoma in nine cases and to focal nodular hyperplasia in two cases. CONCLUSION: In our series, the major HCA subtype was HNF1α-inactivated HCA. We found a low incidence of inflammatory-type HCA. Our data also showed that ß-catenin-activated hepatocellular neoplasms, including cases with atypical histology, constituted a relatively high proportion of the cases. These findings are in contrast to those of most other studies of HCA subtypes.

PD-L1 Expression in Mismatch Repair-deficient Endometrial Carcinoma and Tumor-associated Immune Cells: Differences Between MLH1 Methylated and Nonmethylated Subgroups.

Mismatch repair (MMR)-deficient endometrial carcinomas show increased programmed cell death-ligand 1 (PD-L1) expression compared with MMR-intact endometrial carcinomas, but there are limited data regarding PD-L1 expression between sporadic and inherited carcinomas exhibiting MMR loss. Most of the studies investigating PD-L1 expression in endometrial carcinoma have used tissue microarrays and did not examine all tumor blocks. In this study, we analyzed the expression of PD-L1 in resection specimens of 176 consecutive endometrial carcinomas using all tumor blocks; we compared PD-L1 expression in MMR-deficient endometrial carcinomas, including the MLH1 and PMS2-loss subgroup, and the other MMR-loss subgroups (MSH2 and MSH6, isolated PMS2, and isolated MSH6), with the MMR-intact subgroup. MLH1 methylation was performed in tumors with MLH1 and PMS2 loss. Tumor cell (TC) and tumor-associated immune cell (IC) PD-L1 positivity with a 1% cutoff was observed in 21% (n=37) and 66.5% (n=117) of cases, respectively, and with a 5% cutoff in 5.1% (n=9) and 39.8% (n=70) of cases, respectively. MMR protein deficiency was a statistically significant parameter associated with IC PD-L1 positivity, with 1% and 5% cutoffs on multivariate analysis [odds ratio (OR)=5.236, 95% confidence interval (CI)=2.075-13.211, P=0.001, and OR=3.702, 95% CI=1.759-7.791, P=0.001, respectively]. The multivariate analysis showed that IC PD-L1 positivity, using both 1% and 5% cutoffs, was significantly associated with the MLH1 and PMS2 loss compared with the MMR protein-intact subgroup (MLH1 and PMS2 loss for 1% cutoff: OR=5.104, 95% CI=1.876-13.881, P=0.001, and for 5% cutoff: OR=3.322, 95% CI=1.540-7.166, P=0.002). Squamous differentiation was an independent predictor for TC PD-L1 positivity, with a 5% cutoff (OR=6.102, 95% CI=1.280-10.096, P=0.026). Larger tumor size was an independent predictive factor for IC PD-L1 positivity with a 1% cutoff (OR=6.757, 95% CI=1.569-29.109, P=0.010). Overall, 48 (92.3%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 1% cutoff, and 34 (65.4%) of 52 MLH1 methylated tumors showed IC PD-L1 positivity with 5% cutoff. Our results show a higher rate of IC PD-L1 positivity than in previous studies. This is likely due in part to the use of all tumor blocks. MLH1 and PMS2 loss was an independent predictive factor for IC PD-L1 positivity, with both 1% and 5% cutoffs. Using univariate analysis, we observed decreased disease-free survival for IC PD-L1 positivity ≥5%. Our study results should now be tested and proven in larger cohorts, with longer follow-up data.

Germline pathogenic variant spectrum in 25 cancer susceptibility genes in Turkish breast and colorectal cancer patients and elderly controls.

Inherited pathogenic variants account for 5% to 10% of all breast cancer (BC) and colorectal cancer (CRC) cases. Here, we sought to profile the pathogenic variants in 25 cancer susceptibility genes in Turkish population. Germline pathogenic variants were screened in 732 BC patients, 189 CRC patients and 490 cancer-free elderly controls, using next-generation sequencing-based multigene panel testing and multiplex ligation-dependent probe amplification testing. Pathogenic variants were detected in 17.2% of high-risk BC patients and 26.4% of high-risk CRC patients. More than 95% of these variants were clinically actionable. BRCA1/2 and mismatch repair genes (MLH1, MSH2 and MSH6) accounted for two-thirds of all pathogenic variants detected in high-risk BC and CRC patients, respectively. Pathogenic variants in PALB2, CHEK2, ATM and TP53 were also prevalent in high-risk BC patients (4.5%). BRCA1 exons 17-18 deletion and CHEK2 c.592+3A>T were the most common variants predisposing to BC, and they are likely to be founder variants. Three frequent MUTYH pathogenic variants (c.884C>T, c.1437_1439delGGA and c.1187G>A) were responsible for all MUTYH biallelic cases (4.4% of high-risk CRC patients). The total pathogenic variant frequency was very low in controls (2.4%) and in low-risk BC (3.9%) and CRC (6.1%) patients. Our study depicts the pathogenic variant spectrum and prevalence in Turkish BC and CRC patients, guiding clinicians and health authorities for genetic testing applications and variant classification in Turkish population.

Vaginal epithelioid malignant peripheral nerve sheath tumor nearly misdiagnosed as advanced cervical cancer: A case report.

A 56-year-old woman was referred to our hospital with a pathological diagnosis of squamous cell carcinoma of the cervix. We performed a re-biopsy of the vaginal mass and cervical conization. The mass was originally reported as an epithelioid MPNST after re-biopsy. Strong diffuse S-100 positivity, epithelioid morphology of the lesion, and negativity to all other immune histochemical markers confirmed the diagnosis of epithelioid MPNST. Cervical conization specimen was negative for any neoplasms.