SMARCB1-deficient sinonasal adenocarcinoma is a rare variant of SWI/SNF-deficient malignancies with SMARCB1 loss and adenocarcinoma features. More than 200 high-grade epithelial sinonasal malignancies were retrieved. A total of 14 cases exhibited complete SMARCB1 (INI1) loss and glandular differentiation. SMARCA2 and SMARCA4 were normal, except for one case with a loss of SMARCA2. Next-generation sequencing (NGS) and/or fluorescence in situ hybridization (FISH) revealed an alteration in the SMARCB1 gene in 9/13 cases, while 2/13 were negative. Two tumors harbored SMARCB1 mutations in c.157C > T p.(Arg53Ter) and c.842G > A p.(Trp281Ter). One harbored ARID1B mutations in c.1469G > A p.(Trp490Ter) and MGA c.3724C > T p.(Arg1242Ter). Seven tumors had a SMARCB1 deletion. One carried an ESR1 mutation in c.644-2A > T, and another carried a POLE mutation in c.352_374del p.(Ser118GlyfsTer78). One case had a PAX3 mutation in c.44del p.(Gly15AlafsTer95). Histomorphology of SMARCB1-deficient adenocarcinoma was oncocytoid/rhabdoid and glandular, solid, or trabecular in 9/14 cases. Two had basaloid/blue cytoplasm and one showed focal signet ring cells. Yolk sac tumor-like differentiation with Schiller-Duval-like bodies was seen in 6/14 cases, with 2 cases showing exclusively reticular-microcystic yolk sac pattern. Follow-up of a maximum of 26 months (median 10 months) was available for 8/14 patients. Distant metastasis to the lung, liver, mediastinum, bone, and/or retroperitoneum was seen in 4/8 cases. Locoregional failure was seen in 75% of patients, with 6/8 local recurrences and 3 cervical lymph node metastases. At the last follow-up, 5 of 8 (62%) patients had died of their disease 2 to 20 months after diagnosis (median 8.2 months), and 3 were alive with the disease. The original diagnosis was usually high-grade non-intestinal-type adenocarcinoma or high-grade myoepithelial carcinoma. A correct diagnosis of these aggressive tumors could lead to improved targeted therapies with potentially better overall disease-specific survival.
- MeSH
- Adenocarcinoma * genetics pathology MeSH
- Diagnosis, Differential MeSH
- DNA-Binding Proteins genetics deficiency MeSH
- Adult MeSH
- SMARCB1 Protein * deficiency genetics MeSH
- In Situ Hybridization, Fluorescence MeSH
- Middle Aged MeSH
- Humans MeSH
- Mutation * MeSH
- Myoepithelioma * genetics pathology MeSH
- Biomarkers, Tumor genetics MeSH
- Paranasal Sinus Neoplasms * genetics pathology MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Neoplasm Grading MeSH
- Transcription Factors * genetics deficiency MeSH
- High-Throughput Nucleotide Sequencing MeSH
- Check Tag
- Adult MeSH
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
Low-grade serous carcinoma (LGSC) may develop from serous borderline tumor (SBT) tissue, where the micropapillary type (mSBT) presents the highest risk for progression. The sensitivity of LGSC to standard chemotherapy is limited, so alternative therapeutic approaches, including targeted treatment, are needed. However, knowledge about the molecular landscape of LGSC and mSBT is limited. A sample set of 137 pathologically well-defined cases (LGSC, 97; mSBT, 40) was analyzed using capture DNA next-generation sequencing (727 genes) and RNA next-generation sequencing (147 genes) to show the landscape of somatic mutations, gene fusions, expression pattern, and prognostic and predictive relevance. Class 4/5 mutations in the main driver genes (KRAS, BRAF, NRAS, ERBB2, USP9X) were detected in 48% (14/29) of mSBT cases and 63% (47/75) of LGSC cases. The USP9X mutation was detected in only 17% of LGSC cases. RNA next-generation sequencing revealed gene fusions in 6 of 64 LGSC cases (9%) and 2 of 33 mSBT cases (9%), and a heterogeneous expression profile across LGSC and mSBT. No molecular characteristics were associated with greater survival. The somatic genomic and transcriptomic profiles of 35 mSBT and 85 LGSC cases are compared for the first time. Candidate oncogenic gene fusions involving BRAF, FGFR2, or NF1 as a fusion partner were identified. Molecular testing of LGSC may be used in clinical practice to reveal therapeutically significant targets.
- MeSH
- Azo Compounds * MeSH
- Genomics MeSH
- Humans MeSH
- Mutation MeSH
- Ovarian Neoplasms * diagnosis genetics MeSH
- Proto-Oncogene Proteins B-raf genetics MeSH
- RNA MeSH
- Cystadenocarcinoma, Serous * diagnosis genetics MeSH
- Gene Expression Profiling MeSH
- Neoplasm Grading MeSH
- Ubiquitin Thiolesterase genetics MeSH
- Check Tag
- Humans MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
BACKGROUND/AIM: To test the correlation of 68Ga-PSMA-11 uptake and the expression of PSMA (prostatic specific membrane antigen) with the Gleason score, apparent diffusion coefficient (ADC) and pharmacokinetic parameters obtained from dynamic contrast agent-enhanced MRI/PET. PATIENTS AND METHODS: Forty newly diagnosed, therapy naïve patients with prostatic carcinoma (PC) (mean age of 56.7, range=34-79), who were referred for 68Ga-PSMA-11-PET/MRI for primary staging and had undergone radical prostatectomy (RAPE) were included in this prospective study. Their blood samples were tested for serum levels of prostate-specific antigen (PSA) and proPSA. The patients' prostates were evaluated using whole-mount sections, which helped determine the extent and grade of the tumor; tests were performed to determine immunohistochemical PSMA expression. RESULTS: A correlation between PSMA expression and the accumulation of 68Ga-PSMA-11 was found using the Spearman correlation coefficient (p=0.0011). A stronger correlation was found between Gleason patterns 3 or 4 and PSMA expression (p=0.06). Furthermore, the correlation of Gleason score with the overall 68Ga-PSMA-11 accumulation within the tumor or non-tumor tissue was found to be significant (p=0.0157). A significant relation was found only with the Kep elimination rate constant, which was stronger in Gleason pattern 4 than in Gleason pattern 3. A weaker correlation was found between the accumulation of 68Ga-PSMA-11 and Ktrans in Gleason pattern 4: the most significant relation being between ADCmin and Gleason pattern 3 and 4 (p=0.0074). The total size of the tumor correlated with levels of proPSA (p<0.0001), and its extra prostatic extension correlated with levels of proPSA (p<0.0001). CONCLUSION: 68Ga-PSMA-11 correlates well with the expression of PSMA. Gleason pattern 3 and 4 had a higher correlation with 68Ga-PSMA-11 levels than did Gleason pattern 5. Either no correlation, or a weak correlation, was established with pharmacokinetics.
- MeSH
- Edetic Acid MeSH
- Carcinoma * MeSH
- Middle Aged MeSH
- Humans MeSH
- Magnetic Resonance Imaging MeSH
- Prostatic Neoplasms * diagnostic imaging surgery metabolism MeSH
- Oligopeptides MeSH
- Positron Emission Tomography Computed Tomography MeSH
- Positron-Emission Tomography MeSH
- Prospective Studies MeSH
- Prostate pathology MeSH
- Gallium Radioisotopes MeSH
- Neoplasm Grading MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Some high-risk prostate cancer (PCa) patients may show more favorable Gleason pattern at radical prostatectomy (RP) than at biopsy. OBJECTIVE: To test whether downgrading could be predicted accurately. DESIGN, SETTING, AND PARTICIPANTS: Within the Surveillance, Epidemiology and End Results database (2010-2016), 6690 National Comprehensive Cancer Network (NCCN) high-risk PCa patients were identified. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: We randomly split the overall cohort between development and validation cohorts (both n = 3345, 50%). Multivariable logistic regression models used biopsy Gleason, prostate-specific antigen, number of positive prostate biopsy cores, and cT stage to predict downgrading. Accuracy, calibration, and decision curve analysis (DCA) tested the model in the external validation cohort. RESULTS AND LIMITATIONS: Of 6690 patients, 50.3% were downgraded at RP, and of 2315 patients with any biopsy pattern 5, 44.1% were downgraded to RP Gleason pattern ≤4 + 4. Downgrading rates were highest in biopsy Gleason pattern 5 + 5 (84.1%) and lowest in 3 + 4 (4.0%). In the validation cohort, the logistic regression model-derived nomogram predicted downgrading with 71.0% accuracy, with marginal departures (±3.3%) from ideal predictions in calibration. In DCA, a net benefit throughout all threshold probabilities was recorded, relative to treat-all or treat-none strategies and an algorithm based on an average downgrading rate of 50.3%. All steps were repeated in the subgroup with any biopsy Gleason pattern 5, to predict RP Gleason pattern ≤4 + 4. Here, a second nomogram (n = 2315) yielded 68.0% accuracy, maximal departures from ideal prediction of ±5.7%, and virtually the same DCA pattern as the main nomogram. CONCLUSIONS: Downgrading affects half of all high-risk PCa patients. Its presence may be predicted accurately and may help with better treatment planning. PATIENT SUMMARY: Downgrading occurs in every second high-risk prostate cancer patients. The nomograms developed by us can predict these probabilities accurately.
- MeSH
- Humans MeSH
- Prostatic Neoplasms * surgery pathology MeSH
- Nomograms * MeSH
- Prostate pathology MeSH
- Prostatectomy methods MeSH
- Neoplasm Grading MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Previous cancer-specific mortality (CSM) analyses for different Gleason patterns in Gleason grade group (GGG) 5 cancer were limited by sample size. OBJECTIVE: To test for differences in CSM according to biopsy GG 5 patterns (4 + 5 vs 5 + 4 vs 5 + 5) among patients undergoing radical prostatectomy (RP) or external beam radiation therapy (EBRT). DESIGN, SETTING, AND PARTICIPANTS: Patients in the Surveillance, Epidemiology and End Results database treated with RP and EBRT (2004-2016) were identified and stratified according to Gleason 4 + 5 versus 5 + 4 versus 5 + 5. INTERVENTION: RP or EBRT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Kaplan-Meier and multivariable Cox regression models predicting CSM were constructed. RESULTS AND LIMITATIONS: Of 17 263 eligible patients with GG 5 cancer at biopsy (RP: n = 7208; EBRT: n = 10 055), 12 705 had Gleason 4 + 5, 3302 had Gleason 5 + 4, and 1256 had Gleason 5 + 5 disease. Median age, prostate-specific antigen (PSA) at diagnosis, and advanced cT and cN stages significantly differed by Gleason pattern (Gleason 4 + 5 vs 5 + 4 vs 5 + 5; all p < 0.001). The 10-yr CSM rate was 18.2% for Gleason 4 + 5, 28.0% for Gleason 5 + 4, and 39.1% for Gleason 5 + 5 (p < 0.001). In multivariable analyses for the entire cohort adjusted for PSA, age at diagnosis, and cT and cN stage, Gleason 5 + 4 and Gleason 5 + 5 were associated with 1.6- and 2.2-fold higher CSM, respectively, relative to Gleason 4 + 5. In addition, Gleason 5 + 4 and Gleason 5 + 5 were associated with 1.6- and 2.5-fold, and 1.5- and 2.1-fold higher CSM rates in the RP and EBRT subgroups, respectively, relative to Gleason 4 + 5 (all p < 0.001). CONCLUSIONS: For patients with biopsy GG 5 prostate cancer treated with RP or EBRT, there are important CSM differences by Gleason pattern (4 + 5 vs 5 + 4 vs 5 + 5). Ideally, the individual Gleason pattern should be considered in pretreatment risk stratification. PATIENT SUMMARY: For patients with grade 5 prostate cancer, we found differences in cancer-specific death rates according to the pattern of abnormal cells in the prostate, called the Gleason score. The highest death rate was found for a Gleason pattern score of 5 + 5, followed by Gleason 5 + 4 and then Gleason 4 + 5. These differences were observed for both patients who were treated with prostate removal and patients who underwent radiotherapy.
- MeSH
- Biopsy MeSH
- Humans MeSH
- Prostatic Neoplasms * diagnosis radiotherapy surgery MeSH
- Prostate pathology MeSH
- Prostatectomy methods MeSH
- Prostate-Specific Antigen * MeSH
- Neoplasm Grading MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
INTRODUCTION: There are questions regarding whether grade group (GG) 4 prostate cancer (PC) is heterogeneous in terms of prognosis. We assessed prognostic differences in PC patients within GG 4 treated with radical prostatectomy (RP). MATERIAL AND METHODS: Biochemical recurrence (BCR)-free, cancer-specific, and overall survival were analyzed in 787 PC patients with GG 4 based on RP pathology (Gleason score (GS) 3 + 5: 189, GS 4 + 4: 500, and GS 5 + 3: 98). Logistic regression analysis was performed to assess factors predictive of high-risk surgical pathological features. Cox regression models were used to evaluate potential prognostic factors of survival. RESULTS: Within a median follow-up of 86 months, 378 patients (48.0%) experienced BCR and 96 patients (12.2%) died, 42 of whom (5.3%) died of PC. GS 5 + 3 was significantly associated with worse BCR-free and cancer-specific survival, as well as higher positive surgical margin, lymph node metastasis, extraprostatic extension, and non-organ-confined disease rates, than GS 3 + 5 and higher positive surgical margin, lymph node metastasis, extraprostatic extension, and non-organ-confined disease rates than GS 4 + 4 (P < 0.05). GS 4 + 4 was significantly associated with worse BCR-free survival and higher extraprostatic extension, and non-organ-confined disease rates than GS 3 + 5 (P < 0.05). Inclusion of the different Gleason patterns improved the discrimination of a model for prediction of all survival outcomes compared to standard prognosticators. CONCLUSIONS: There is considerable heterogeneity within GG 4 in terms of oncological and surgical pathological outcomes. Primary and secondary Gleason patterns should be considered to stratify high-risk PC patients after RP.
- MeSH
- Middle Aged MeSH
- Humans MeSH
- Neoplasm Recurrence, Local pathology MeSH
- Survival Rate MeSH
- Prostatic Neoplasms mortality pathology surgery MeSH
- Prognosis MeSH
- Prostatectomy * MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Neoplasm Grading MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged, 80 and over MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
BACKGROUND: Grade group (GG) 4 prostate cancer (PC) is considered a single entity; however, there are questions regarding prognostic heterogeneity. This study assessed the prognostic differences among various Gleason scores (GSs) classified as GG 4 PC on biopsy before radical prostatectomy (RP). METHODS: We conducted a multicenter retrospective study, and a total of 1791 patients (GS 3 + 5: 190; GS 4 + 4: 1557; and GS 5 + 3: 44) with biopsy GG 4 were included for analysis. Biochemical recurrence (BCR)-free survival, cancer-specific survival, and overall survival were analyzed using the Kaplan-Meier method and the log-rank test. Logistic regression analysis was performed to identify factors associated with high-risk surgical pathologic features. Cox regression models were used to analyze time-dependent oncologic endpoints. RESULTS: Over a median follow-up of 75 months, 750 patients (41.9%) experienced BCR, 146 (8.2%) died of any causes, and 57 (3.2%) died of PC. Biopsy GS 5 + 3 was associated with significantly higher rates of GS upgrading in RP specimens than GS 3 + 5 and GS 4 + 4. On multivariable analysis adjusted for clinicopathologic features, different GSs within GG 4 were significantly associated with BCR (p = 0.03) but not PC-specific or all-cause mortality. Study limitations include the lack of central pathological specimen evaluation. CONCLUSIONS: Patients with GG 4 at biopsy exhibited some limited biological and clinical heterogeneity. Specifically, GS 5 + 3 had an increased risk of GS upgrading. This can help individualize patients' counseling and encourage further study to refine biopsy specimen-based GG classification.
- MeSH
- Biopsy MeSH
- Humans MeSH
- Prostatic Neoplasms * surgery MeSH
- Prognosis MeSH
- Prostatectomy * MeSH
- Prostate-Specific Antigen MeSH
- Retrospective Studies MeSH
- Neoplasm Grading MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Multicenter Study MeSH
BACKGROUND: We hypothesized that Gleason Grade Group (GGG) IV patients treated with radical prostatectomy (RP) or external beam radiotherapy (EBRT) exhibit different cancer-specific mortality (CSM) rates according to underlying Gleason patterns (GP): 4 + 4 versus 3 + 5 versus 5 + 3. MATERIALS AND METHODS: We identified all GGG IV patients treated with either RP or EBRT within the Surveillance, Epidemiology, and End Results 2004-2016 database. The effect of biopsy GP on CSM (3 + 5 vs. 4 + 4 vs. 5 + 3) was tested in Kaplan-Meier and multivariable competing risks regression models (adjusted for PSA, age at diagnosis, cT-, and cN-stage). RESULTS: Of 26,458 GGG IV patients, 14,203 (53.7%) were treated with EBRT and 12,255 (46.3%) with RP. Of RP patients, 15.3 versus 81.2 versus 3.4% exhibited biopsy GP 3 + 5 versus 4 + 4 versus 5 + 3 and respective 10-year CSM rates were 6.5 versus 6.2 versus 12.6% (p < .001). In multivariable analyses addressing RP patients, GP 5 + 3 was associated with two-fold higher CSM rate than GP 4 + 4 (p < .001), but not GP 3 + 5 (p = .1). Of EBRT patients, 7.6 versus 89.8 versus 2.6% exhibited biopsy GP 3 + 5 versus 4 + 4 versus 5 + 3 and respective 10-year CSM rates were 12.2 versus 13.8 versus 17.8% (p < .001). In multivariable analyses addressing EBRT patients, no CSM differences according to GP were observed (all p ≥ .4). CONCLUSION: In GGG IV RP candidates, the presence of biopsy GP 5 + 3 purports a significantly higher CSM than in GP 4 + 4 or 3 + 5. In GGG IV EBRT candidates, no significant CSM differences according to GP were recorded.
- MeSH
- Biopsy MeSH
- Middle Aged MeSH
- Humans MeSH
- Prostatic Neoplasms mortality pathology therapy MeSH
- SEER Program MeSH
- Prostatectomy statistics & numerical data MeSH
- Prostate-Specific Antigen blood MeSH
- Radiotherapy methods statistics & numerical data MeSH
- Aged MeSH
- Neoplasm Grading * MeSH
- Treatment Outcome MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
INTRODUCTION: This systematic review and meta-analysis was conducted to assess the prognostic differences between different Gleason patterns in patients with prostate cancer (PC) within Internal Society of Urological Pathology (ISUP) grade group 4 (GG 4). EVIDENCE ACQUISITION: PUBMED and Scopus databases were searched for articles published prior to December 2019 according to the Preferred Reporting Items for Systematic Review and Meta-analysis statement. Studies were deemed eligible if they compared overall survival (OS), cancer-specific survival (CSS), and surgical pathological outcomes in PC patients categorized as ISUP GG 4 (Gleason Score [GS] 4+4 vs. GS 3+5 or GS 5+3). Formal meta-analyses were performed for these outcomes. EVIDENCE SYNTHESIS: Ten studies with 42,041 patients were eligible for the systematic review and eight studies with 36,250 patients for meta-analysis. The treatment type of included study was three surgery and three radiotherapy. The other four studies included many kinds of treatments such as surgery, radiotherapy, androgen deprivation therapy, and chemotherapy. GS 4+4 was significantly associated with better OS (pooled hazard ratio (HR): 0.52, 95% confidential interval (CI): 0.29-0.91) than GS 3+5 or GS 5+3. Positive surgical margin rates were significantly lower with GS 4+4 than GS 3+5 and GS 5+3 (odds ratio [OR] 0.70/95% CI 0.64-0.77 and OR 0.70/95% CI 0.56-0.87, respectively). In contrast, different Gleason patterns in ISUP GG 4 were not significantly associated with CSS (pooled HR: 0.77, 95% CI: 0.56-1.06). CONCLUSIONS: GS 4+4 in patients with PC was associated with better OS and positive surgical margin rates. It seems likely that there is heterogeneity within ISUP GG 4. However, caution should be exercised in interpreting the conclusions drawn from this study, given the limitations of the study, which include the heterogeneity of the population of interest and the retrospective nature of the primary data evaluated.
- MeSH
- Survival Analysis MeSH
- Humans MeSH
- Prostatic Neoplasms diagnosis pathology MeSH
- Prognosis MeSH
- Neoplasm Grading * MeSH
- Treatment Outcome MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Publication type
- Journal Article MeSH
- Meta-Analysis MeSH
- Systematic Review MeSH
Diagnosis of salivary gland neoplasms is often challenging due to their high morphological diversity and overlaps. Several recurrent molecular alterations have been described recently, which can serve as powerful diagnostic tools and potential therapeutic targets (e.g. NTRK or RET fusions). However, current sequential molecular testing can be expensive and time consuming. In order to facilitate the diagnosis of salivary gland neoplasms, we designed an all-in-one RNA-based next generation sequencing panel suitable for the detection of mutations, fusions and gene expression levels (including NR4A3) of 27 genes involved in salivary gland neoplasms. Here we present the validation of the "SalvGlandDx" panel on FFPE histological specimen including fine needle aspiration (FNA) cell block material, against the standard methods currently used at our institution. In a second part we describe selected unique cases in which the SalvGlandDx panel allowed proper diagnosis and new insights into special molecular characteristics of selected salivary gland tumors. We characterize a unique salivary gland adenocarcinoma harboring a ZCCHC7-NTRK2 fusion, a highly uncommon spindle cell and pseudoangiomatoid adenoid-cystic carcinoma with MYBL1-NFIB fusion, and a purely oncocytic mucoepidermoid carcinoma, whereas diagnosis could be made by detection of a CRTC3-MAML2 rearrangement on the cell block specimen of the FNA. Further, a rare case of a SS18-ZBTB7A rearranged low-grade adenocarcinoma previously described as potential spectrum of microsecretory adenocarcinoma, is reported. In addition, features of six cases within the spectrum of polymorphous adenocarcinoma / cribriform adenocarcinoma of salivary gland including PRKD1 p.E710D mutations and novel fusions involving PRKAR2A-PRKD1, SNX9-PRKD1 and ATL2-PRKD3, are described.
- MeSH
- Biopsy MeSH
- Oncogene Proteins, Fusion genetics metabolism MeSH
- In Situ Hybridization, Fluorescence MeSH
- Immunohistochemistry methods MeSH
- Humans MeSH
- Mutation MeSH
- Biomarkers, Tumor * MeSH
- Cell Line, Tumor MeSH
- Salivary Gland Neoplasms diagnosis drug therapy genetics MeSH
- Neoplasm Staging MeSH
- Gene Expression Profiling * methods MeSH
- Neoplasm Grading MeSH
- High-Throughput Nucleotide Sequencing * methods MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH