To assess the value of the PI-RADS 2.1 scoring system in the detection of prostate cancer on multiparametric MRI in comparison to the standard PI-RADS 2.0 system and to assess its inter-reader ...variability. This IRB-approved study included 229 patients undergoing multiparametric prostate MRI prior to MRI-guided TRUS-based biopsy, which were retrospectively recruited from our prospectively maintained institutional database. Two readers with high (reader 1, 6 years) and low (reader 2, 2 years) level of expertise identified the lesion with the highest PI-RADS score for both version 2.0 and 2.1 for each patient. Inter-reader agreement was estimated, and diagnostic accuracy analysis was performed. Inter-reader agreement on PI-RADS scores was fair for both version 2.0 (kappa: 0.57) and 2.1 (kappa: 0.51). Detection rates for prostate cancer (PCa) and clinically significant prostate cancer (csPCa) were almost identical for both PI-RADS versions and higher for the more experienced reader (AUC, Reader 1: PCa, 0.881-0.887, csPCa, 0.874-0.879; Reader 2: PCa, 0.765, csPCa, 0.746-0.747; both p > 0.05), both when using a PI-RADS score of greater than or equal to 4 and greater than or equal to3 as indicators for positivity for cancer. The new PI-RADS 2.1 scoring system showed comparable diagnostic performance and inter-reader variability compared to version 2.0. The introduced changes in the version 2.1 seem only to take effect in a very small number of patients.
We evaluated the diagnostic accuracy of multiparametric magnetic resonance imaging and multiparametric magnetic resonance imaging/transrectal ultrasound fusion guided targeted biopsy against that of ...transperineal template saturation prostate biopsy to detect prostate cancer.
We retrospectively analyzed the records of 415 men who consecutively presented for prostate biopsy between November 2014 and September 2016 at our tertiary care center. Multiparametric magnetic resonance imaging was performed using a 3 Tesla device without an endorectal coil, followed by transperineal template saturation prostate biopsy with the BiopSee® fusion system. Additional fusion guided targeted biopsy was done in men with a suspicious lesion on multiparametric magnetic resonance imaging, defined as Likert score 3 to 5. Any Gleason pattern 4 or greater was defined as clinically significant prostate cancer. The detection rates of multiparametric magnetic resonance imaging and fusion guided targeted biopsy were compared with the detection rate of transperineal template saturation prostate biopsy using the McNemar test.
We obtained a median of 40 (range 30 to 55) and 3 (range 2 to 4) transperineal template saturation prostate biopsy and fusion guided targeted biopsy cores, respectively. Of the 124 patients (29.9%) without a suspicious lesion on multiparametric magnetic resonance imaging 32 (25.8%) were found to have clinically significant prostate cancer on transperineal template saturation prostate biopsy. Of the 291 patients (70.1%) with a Likert score of 3 to 5 clinically significant prostate cancer was detected in 129 (44.3%) by multiparametric magnetic resonance imaging fusion guided targeted biopsy, in 176 (60.5%) by transperineal template saturation prostate biopsy and in 187 (64.3%) by the combined approach. Overall 58 cases (19.9%) of clinically significant prostate cancer would have been missed if fusion guided targeted biopsy had been performed exclusively. The sensitivity of multiparametric magnetic resonance imaging and fusion guided targeted biopsy for clinically significant prostate cancer was 84.6% and 56.7% with a negative likelihood ratio of 0.35 and 0.46, respectively.
Multiparametric magnetic resonance imaging alone should not be performed as a triage test due to a substantial number of false-negative cases with clinically significant prostate cancer. Systematic biopsy outperformed fusion guided targeted biopsy. Therefore, it will remain crucial in the diagnostic pathway of prostate cancer.
ETV6 gene abnormalities are well described in tumor pathology. Many fusion partners of ETV6 have been reported in a variety of epithelial, mesenchymal, and hematological malignancies. In salivary ...gland tumor pathology, however, the ETV6-NTRK3 translocation is specific for (mammary analog) secretory carcinoma, and has not been documented in any other salivary tumor type. The present study comprised a clinical, histologic, and molecular analysis of 10 cases of secretory carcinoma, with typical morphology and immunoprofile harboring a novel ETV6-RET translocation.
The landscape of salivary gland carcinomas is ever-changing, with a growing list of new tumors and newly elucidated variants of well-known tumor entities. The routine use of next-generation ...sequencing has been instrumental in identifying novel fusions and tumor entities, which has helped bring the classification to a more objective and evidenced-based model. However, morphology remains critical in assessing the validity of these novel molecular findings, and most importantly, in assessing which of these findings will have an impact on the prognosis and treatment decisions for patients. The recognition of microsecretory adenocarcinoma (MSA) as a distinct low-grade malignancy of salivary glands, underpinned by MEF2C::SS18 , and a single possibly related case of SS18::ZBTB7A , recently expanded this growing list of distinctive tumors. It was not until now, however, that the morphology of the latter case was known to be unique and reproducible. The authors have now seen 4 of these distinctive tumors that show a combination of distinctive oncocytic cells forming compact glandular growth as well as amphophilic cells forming tubular growth, and suggest the appellation "microcribriform adenocarcinoma" (MCA). So far, these tumors appear to preferentially occur in nonoral sites (2 parotid, 1 submandibular gland, and 1 bronchial seromucous glands). By immunohistochemistry, they express S100 and SOX-10 with focal outer myoepithelial cells marked by circumferential p63, p40, and smooth muscle actin staining around some of the nests and tubules. The tumors show infiltrative growth within a hyalinized and myxoid stroma. Cytologically, they appear generally low grade, similar to MSA. The morphologic and molecular uniformity of these 4 microcribriform adenocarcinoma cases warrants their recognition, and while related to MSA, they are sufficiently different to be classified as a distinct tumor. So far, in limited follow-up, these tumors appear to be relatively indolent.
Formalin‐fixed, paraffin‐embedded (FFPE), biobanked tissue samples offer an invaluable resource for clinical and biomarker research. Here, we developed a pressure cycling technology (PCT)‐SWATH mass ...spectrometry workflow to analyze FFPE tissue proteomes and applied it to the stratification of prostate cancer (PCa) and diffuse large B‐cell lymphoma (DLBCL) samples. We show that the proteome patterns of FFPE PCa tissue samples and their analogous fresh‐frozen (FF) counterparts have a high degree of similarity and we confirmed multiple proteins consistently regulated in PCa tissues in an independent sample cohort. We further demonstrate temporal stability of proteome patterns from FFPE samples that were stored between 1 and 15 years in a biobank and show a high degree of the proteome pattern similarity between two types of histological regions in small FFPE samples, that is, punched tissue biopsies and thin tissue sections of micrometer thickness, despite the existence of a certain degree of biological variations. Applying the method to two independent DLBCL cohorts, we identified myeloperoxidase, a peroxidase enzyme, as a novel prognostic marker. In summary, this study presents a robust proteomic method to analyze bulk and biopsy FFPE tissues and reports the first systematic comparison of proteome maps generated from FFPE and FF samples. Our data demonstrate the practicality and superiority of FFPE over FF samples for proteome in biomarker discovery. Promising biomarker candidates for PCa and DLBCL have been discovered.
Here, we report a pressure cycling technology‐SWATH data‐independent acquisition mass spectrometry workflow to reproducibly analyze punched and sectioned formalin‐fixed, paraffin‐embedded (FFPE) tissue proteomes in high‐throughput fashion. A FFPE tissue biobank can be thereby converted into a digital biobank of comprehensive tissue proteome archives which could be mined perpetually for clinical and biomarker research.
•SalvGlandDx includes 27 genes known to be involved in salivary gland neoplasms•Can be applied to FFPE histological and cytological (cell block) specimen•Solely RNA extraction is needed•Gene fusions, ...hotspot mutations and gene expression levels can be detected•Guides diagnosis in uncertain cases and can detect therapeutically relevant fusions
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.
Intraductal carcinoma (IC) is the new WHO designation for tumors previously encompassed by "low-grade cribriform cystadenocarcinoma" and "low-grade salivary duct carcinoma." The relationship of IC to ...salivary duct carcinoma (SDC) is controversial, even though they are considered to be distinct entities. IC is a rare low-grade malignant salivary gland neoplasm with histopathological features reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast, showing diffuse S100 protein and mammaglobin positivity, while it is partially defined genetically. Recently, RET rearrangements including NCOA4-RET and TRIM27-RET have been described in IC. Here, we genetically characterize the largest cohort of IC to date (33 cases) including 8 cases with focal or widespread invasive growth and 1 case with lymph node metastasis. Thirty-three cases of IC were analyzed by next-generation sequencing (NGS) using the FusionPlex Solid Tumor kit (ArcherDX). Identified gene fusions were confirmed using fluorescence in situ hybridization break-apart and fusion probes and an reverse transcription polymerase chain reaction designed specifically for the detected breakpoints. Ten cases of SDC were analyzed for comparison using NGS panels that detect mutations and fusion transcripts. NGS analysis detected an NCOA4-RET fusion transcript in 11 cases of intercalated duct-type IC joining exon 7 or 8 of NCOA4 gene and exon 12 of the RET gene. Eight cases of IC had an invasive growth pattern, including one with widespread invasion and lymph node metastasis. Three invasive ICs harbored an NCOA4-RET fusion transcript, while 1 case was negative, and 2 cases were not analyzable. In addition, a novel TRIM27-RET fusion transcript between exon 3 of TRIM27 and exon 12 of RET was identified in 2 cases of IC with apocrine features, and one of them displayed invasive growth. Two IC cases with invasive growth harbored novel fusions TUT1-ETV5 and KIAA1217-RET, respectively. A total of 42.4% of the cases in this series of IC harbored fusions involving RET. Such fusion transcripts were not detected in any of the 10 SDC cases. We have confirmed NCOA4-RET as a predominant fusion in intercalated duct-type IC, including 3 cases with invasive growth pattern. A novel finding in our series was a case of widely invasive intercalated duct-type IC, with a single lymph node metastasis that revealed an NCOA4-RET fusion transcript. We also demonstrated that a subset of apocrine ICs harbored a TRIM27-RET gene fusion, including one case with invasive growth. In contrast, neither NCOA4-RET nor TRIM27-RET fusions were detected in any tested SDCs. Thus, the distinct molecular findings in IC and SDC support that the tumors are separate malignant salivary tumor entities. The presence of tumor-type-specific NCOA4-RET or TRIM27-RET translocations in a subset of widely invasive carcinomas with intercalated duct-like immunoprofiles suggests that a recharacterization of IC including its redesignation as "intercalated duct carcinoma, invasive or noninvasive" may be appropriate.
Defining the exact histological features of salivary gland malignancies before treatment remains an unsolved problem that compromises the ability to tailor further therapeutic steps individually. ...Radiomics, a new methodology to extract quantitative information from medical images, could contribute to characterizing the individual cancer phenotype already before treatment in a fast and non-invasive way. Consequently, the standardization and implementation of radiomic analysis in the clinical routine work to predict histology of salivary gland cancer (SGC) could also provide improvements in clinical decision-making. In this study, we aimed to investigate the potential of radiomic features as imaging biomarker to distinguish between high grade and low-grade salivary gland malignancies. We have also investigated the effect of image and feature level harmonization on the performance of radiomic models. For this study, our dual center cohort consisted of 126 patients, with histologically proven SGC, who underwent curative-intent treatment in two tertiary oncology centers. We extracted and analyzed the radiomics features of 120 pre-therapeutic MRI images with gadolinium (T1 sequences), and correlated those with the definitive post-operative histology. In our study the best radiomic model achieved average AUC of 0.66 and balanced accuracy of 0.63. According to the results, there is significant difference between the performance of models based on MRI intensity normalized images + harmonized features and other models (p value < 0.05) which indicates that in case of dealing with heterogeneous dataset, applying the harmonization methods is beneficial. Among radiomic features minimum intensity from first order, and gray level-variance from texture category were frequently selected during multivariate analysis which indicate the potential of these features as being used as imaging biomarker. The present bicentric study presents for the first time the feasibility of implementing MR-based, handcrafted radiomics, based on T1 contrast-enhanced sequences and the ComBat harmonization method in an effort to predict the formal grading of salivary gland carcinoma with satisfactory performance.