Expanding the spectrum of low-grade sinonasal adenocarcinoma with biphasic seromucinous differentiation and activating HRAS/AKT1 mutations.

AIMS: Low-grade non-intestinal-type sinonasal adenocarcinoma (LGSNAC) is a rare heterogeneous and poorly characterised group of tumours, distinct from intestinal- and salivary-type neoplasms. Therefore, further characterisation is needed for clearer biological understanding and classification. METHODS AND RESULTS: Clinical, histological and molecular characterisation of four cases of biphasic, low-grade adenocarcinomas of the sinonasal tract was performed. All patients were male, aged between 48 and 78 years, who presented with polypoid masses in the nasal cavity. Microscopically, virtually all tumours were dominated by tubulo-glandular biphasic patterns, microcystic, focal (micro)papillary, oncocytic or basaloid features. Immunohistochemical staining confirmed biphasic differentiation with an outer layer of myoepithelial cells. Molecular profiling revealed HRAS (p.G13R, p.Q61R) mutations, and concomitant AKT1 (p.E17K, p.Q79R) mutations in two cases. Two cases showed potential in-situ/precursor lesions adjacent to the tumour. Follow-up periods ranged from 1 to 30 months, with one case relapsing locally after 12 and > 20 years. CONCLUSION: This study further corroborates a distinct biphasic low-grade neoplasm of the sinonasal tract with seromucinous differentiation. Although morphological and molecular features overlap with salivary gland epithelial-myoepithelial carcinoma, several arguments favour categorising these tumours within the spectrum of LGSNAC.

Focal therapy with high-intensity focused ultrasound for prostate cancer: 3-year outcomes from a prospective trial.

OBJECTIVE: To assess the oncological and functional outcomes of focal high-intensity focused ultrasound (HIFU) in treating localised prostate cancer (PCa), a 3-year prospective study was undertaken using periodic post-ablation saturation biopsies. PATIENTS AND METHODS: Men with two or fewer lesions of grade group (GG) ≤3 PCa were eligible for participation. Additional criteria included a prostate-specific antigen (PSA) level of ≤15 ng/mL, clinical T1c-T2, and a life expectancy of ≥10 years. The primary endpoint was failure-free survival (FFS), defined as absence of clinically significant PCa (csPCa) in- or out-of-field on protocol-mandated saturation biopsy, no whole-gland or systemic salvage treatment, PCa metastasis, or PCa-related death. Results are reported using two distinct definitions of csPCa: (i) the presence of any GG ≥2 and (ii) any GG ≥3 or core involvement of ≥6 mm. Secondary endpoints were functional patient-reported outcome measures addressing urinary, sexual, and bowel function. RESULTS: A total of 91 patients were included: six (7%) with GG1 and 85 (93%) with GG ≥2. In all, 83 (91%) underwent at least one follow-up biopsy. Biopsy attendance at 6, 12, and 36 months was 84%, 67%, and 51%, respectively. The FFS at these time points for any GG ≥2 PCa was 79% (95% confidence interval [CI] 80-88%), 57% (95% CI 48-69%) and 44% (95% CI 34-56%), respectively. Using the second definition, FFS were 88% (95% CI 81-95%), 70% (95% CI 61-81%) and 65% (95% CI 55-77%), respectively. The 3-year cancer-specific survival was 100%, and freedom from metastasis was 99%. Magnetic resonance imaging (MRI) (negative predictive value of up to 89%, 95% CI 84-93%) and relative decrease of PSA values (P = 0.4) performed poorly in detecting residual disease. Urinary and bowel assessment returned to baseline questionnaire scores within 3 months. In all, 17 (21%) patients reported meaningful worsening in erectile function. A significant decrease of PCa related anxiety was observed. CONCLUSIONS: Focal HIFU treatment for localised PCa shows excellent functional outcomes with half of the patients remaining cancer-free after 3 years. Whole-gland treatment was avoided in 81%. Early follow-up biopsies are crucial to change or continue the treatment modality at the right time, while the use of MRI and PSA in detecting PCa recurrence is uncertain.

Updates in head and neck cytopathology: Insights from European Congress of Pathology Short Course.

Cytological specimens play a pivotal role in head and neck nodule/mass work up and diagnoses. The specimens´ importance has grown with the onset of personalized medicine and the routine use of molecular markers in the diagnostic work up. The Updates in Head and Neck Cytopathology Short Course ran during the 35th European Congress of Pathology held in Dublin, Ireland, in 2023 and brought together experts in cytopathology, pathology, and related fields to share their expertise and experience in the field of head and neck cytopathology and its future directions. Topics such as a one-stop clinic, the Milan System for Reporting Salivary Gland Cytopathology, next generation sequencing, and human papilloma virus detection in the head and neck area were covered during the short course. These topics are briefly summarized in the present review.

Molecular testing in salivary gland cytopathology: A practical overview in conjunction with the Milan system.

Recently, significant advances in the molecular characterization of salivary gland neoplasms have facilitated the classification and diagnosis of specific diagnostic entities. In the highly challenging diagnostic scenario of salivary malignancies, molecular testing is increasingly being adopted in routine practice to refine the cytological diagnosis of salivary lesions. Here, we reviewed the most recent evidence in the field of salivary glands molecular cytopathology.

Clinical predictors of negative/equivocal SPECT imaging outcomes in primary hyperparathyroidism: Factors calling for 18F-choline-PET.

PURPOSE: For minimally invasive surgery of parathyroid adenomas, exact localization diagnostics are essential. Main imaging modalities used for diagnostics are sonography, SPECT with/without CT (traditional imaging) and 18F-choline-PET. The aim of our study was to identify predictors for inconclusive SPECT imaging and subsequently determine in which cases 18F-choline-PET is needed. METHODS: Retrospective analysis of 138 patients with histologically confirmed primary hyperparathyroidism (pHPT). After sonography, patients underwent SPECT or SPECT/CT imaging, with subsequent 18F-choline-PET in cases of disconcordant results. Logistic regression analysis was used to identify clinical and laboratory factors predictive for negative SPECT results. RESULTS: Sensitivity rates for sonography, SPECT, SPECT/CT, and choline-PET were 47 %, 49 %, 71.7 %, and 97 %, respectively. Logistic regression revealed lower PTH levels (p < 0.001), presence of structural thyroid disease (p = 0.018), and negative sonography (p < 0.001) as predictive of negative/equivocal SPECT outcome. An additional traditional imaging CT scan to a SPECT enhanced detection odds, as did greater adenoma weight. Urolithiasis, osteoporosis, and calcium values as measurement of activity and duration of disease showed no significant association with the detection rate. Furthermore, our study demonstrated that 18F-choline-PET exhibited remarkable sensitivity in detecting adenomas among patients with negative/equivocal SPECT results. CONCLUSION: Our study reveals potential predictive factors for a negative/equivocal SPECT outcome in pHPT. Identifying these factors might allow minimizing futile SPECT examinations and perhaps encourage timely utilization of 18F-choline-PET imaging. Our study reinforces the clinical significance of 18F-choline-PET, especially in complex cases with disconcordant results by conventional parathyroid imaging methods.

Development and external validation of a multivariable [68Ga]Ga-PSMA-11 PET-based prediction model for lymph node involvement in men with intermediate or high-risk prostate cancer.

PURPOSE: To develop and evaluate a lymph node invasion (LNI) prediction model for men staged with [68Ga]Ga-PSMA-11 PET. METHODS: A consecutive sample of intermediate to high-risk prostate cancer (PCa) patients undergoing [68Ga]Ga-PSMA-11 PET, extended pelvic lymph node dissection (ePLND), and radical prostatectomy (RP) at two tertiary referral centers were retrospectively identified. The training cohort comprised 173 patients (treated between 2013 and 2017), the validation cohort 90 patients (treated between 2016 and 2019). Three models for LNI prediction were developed and evaluated using cross-validation. Optimal risk-threshold was determined during model development. The best performing model was evaluated and compared to available conventional and multiparametric magnetic resonance imaging (mpMRI)-based prediction models using area under the receiver operating characteristic curves (AUC), calibration plots, and decision curve analysis (DCA). RESULTS: A combined model including prostate-specific antigen, biopsy Gleason grade group, [68Ga]Ga Ga-PSMA-11 positive volume of the primary tumor, and the assessment of the [68Ga]Ga-PSMA-11 report N-status yielded an AUC of 0.923 (95% CI 0.863-0.984) in the external validation. Using a cutoff of ≥ 17%, 44 (50%) ePLNDs would be spared and LNI missed in one patient (4.8%). Compared to conventional and MRI-based models, the proposed model showed similar calibration, higher AUC (0.923 (95% CI 0.863-0.984) vs. 0.700 (95% CI 0.548-0.852)-0.824 (95% CI 0.710-0.938)) and higher net benefit at DCA. CONCLUSIONS: Our results indicate that information from [68Ga]Ga-PSMA-11 may improve LNI prediction in intermediate to high-risk PCa patients undergoing primary staging especially when combined with clinical parameters. For better LNI prediction, future research should investigate the combination of information from both PSMA PET and mpMRI for LNI prediction in PCa patients before RP.

Need for adjuvant radiotherapy in oral cancer: depth of invasion rather than tumor diameter.

PURPOSE: The 8th edition of the TNM Cancer Staging Manual incorporates depth of invasion (DOI) into the pathologic tumor classification for oral squamous cell carcinoma (OSSC). While deep invading tumors with small tumor diameters (TD) have been categorized as early stage tumors in the 7th edition, they are now upstaged, potentially influencing the decision to initiate adjuvant radiotherapy (RT). METHODS: OSCC patients surgically treated with curative intent between 2010 and 2019 were consecutively included. Tumors were staged based on TD only (according to the 7th edition TNM Cancer Staging Manual), then restaged based solely on DOI. RESULTS: Of the 133 included patients, 58 patients (43.6%) had a different pT-stage when using DOI instead of TD for staging (upstaging in 23.3%). Overall survival (OS) was significantly worse in patients who were upstaged with DOI. In addition, stratification by adjuvant RT showed significant worse OS in upstaged patients without receiving adjuvant RT. CONCLUSIONS: DOI seems to be an import indicator for adjuvant RT in OSCC-patients.

Prediction of extranodal extension in oropharyngeal cancer patients and carcinoma of unknown primary: value of metabolic tumor imaging with hybrid PET compared with MRI and CT.

OBJECTIVES: The aim of this study was to investigate the value of metabolic tumor imaging using hybrid PET for the preoperative detection of extranodal extension (ENE) in lymph node metastases of oropharyngeal squamous cell carcinoma (OPSCC). METHODS: We performed a retrospective analysis of a consecutive cohort of patients with OPSCC treated with primary surgery with or without adjuvant (chemo-) radiotherapy at the Kantonsspital Sankt-Gallen and the University Hospital Zurich, Switzerland, from 2010 until 2019. Hybrid PET was compared to conventional cross-sectional imaging with MRI and CT. Histopathological presence of ENE of neck dissection specimen served as gold standard. RESULTS: A total number of 234 patients were included in the study, 95 (40.6%) of which had pathological ENE (pENE). CT has a good specificity with 93.7%; meanwhile, MRI was the most sensitive diagnostic method (72.0%). The nodal metabolic tumor parameters (SUVmax, TLG, MTV) were significantly higher in patients with positive ENE (p < 0.001 for all three parameters) than in patients with negative ENE (p < 0.001, for all three parameters). CONCLUSIONS: CT achieved the best specificity, while MRI had the best sensitivity to detect ENE. Nodal metabolic tumor parameters differed significantly between ENE-positive/negative and p16-positive/negative patients. Hence, quantitative data obtained by metabolic imaging might predict presence of ENE and, therefore, could be helpful in customizing therapy management.

Expanding the clinicopathological spectrum of TGFBR3-PLAG1 rearranged salivary gland neoplasms with myoepithelial differentiation including evidence of high-grade transformation.

PLAG1 rearrangements have been described as a molecular hallmark of salivary gland pleomorphic adenoma (PA), carcinoma ex pleomorphic adenoma (CEPA), and myoepithelial carcinoma (MECA). Several fusion partners have been described, however, commonly no further assignment to the aforementioned entities or a morphological prediction can be made based on the knowledge of the fusion partner alone. In contrast, TGFBR3-PLAG1 fusion has been specifically described and characterized as an oncogenic driver in MECA, and less common in MECA ex PA. Here, we describe the clinicopathological features of three TGFBR3-PLAG1 fusion-positive salivary gland neoplasms, all of which arose in the deep lobe of the parotid gland. Histopathology showed high morphological similarities, encompassing encapsulation, a polylobular growth pattern, bland basaloid and oncocytoid cells with myoepithelial differentiation, and a distinct sclerotic background. All cases showed at least limited, unusual foci of minimal invasion into adjacent salivary gland tissue, including one case with ERBB2 (Her2/neu) amplified, TP53 mutated high-grade transformation, and lymph node metastases. Of note, all cases illustrated focal ductal differentiation. Classification remains difficult, as morphological overlaps between myoepithelial-rich cellular PA, myoepithelioma, and MECA were observed. However, evidence of minimal invasion advocates classification as low-grade MECA. This case series further characterizes the spectrum of uncommon cellular myoepithelial neoplasms harboring TGFBR3-PLAG1 fusion, which show recurrent minimal invasion of the adjacent salivary gland tissue, a predilection to the deep lobe of the parotid gland, and potential high-grade transformation.

Eosinophilic solid and cystic renal cell carcinoma and renal cell carcinomas with TFEB alterations: a comparative study.

AIMS: Eosinophilic solid and cystic renal cell carcinoma (ESC RCC) is a recently described renal tumour entity with frequent cytokeratin (CK)20 positivity, commonly harbouring TSC mutations. In contrast, frequency of CK20 expression and presence of TSC mutations are unclear in TFEB-amplified RCC and TFEB-translocated RCC, which frequently express Melan A. Herein, we provide a comparative analysis of six ESC RCC with four TFEB-amplified/translocated RCC. METHODS AND RESULTS: We assessed the frequency of CK20 and Melan A expression by immunohistochemistry and of TSC mutations by next-generation sequencing. TFEB alterations were confirmed by fluorescence in-situ hybridisation (FISH). All tumours showed voluminous eosinophilic cells with granular cytoplasm, prominent nucleoli, and most showed admixture of solid and cystic areas. CK20 expression was found in all six ESC RCC and in all RCCs with TFEB alterations. Melan A positivity was identified in five of six ESC RCC and four of four RCC with TFEB alterations. We found TSC mutations in two ESC RCCs, including in one case also harbouring a CIC fusion, and identified a TSC mutation in one TFEB-amplified RCC. CONCLUSIONS: ESC RCC represents an emerging renal tumour entity with some histological, immunohistochemical and molecular overlap to TFEB-amplified/translocated RCC. FISH for TFEB aids in this differential diagnosis in challenging cases.

Infiltrative growth pattern of prostate cancer is associated with lower uptake on PSMA PET and reduced diffusion restriction on mpMRI.

PURPOSE: Recently, a significant association was shown between novel growth patterns on histopathology of prostate cancer (PCa) and prostate-specific membrane antigen (PSMA) uptake on [68Ga]PSMA-PET. It is the aim of this study to evaluate the association between these growth patterns and ADC (mm2/1000 s) values in comparison to [68Ga]PSMA uptake on PET/MRI. METHODS: We retrospectively evaluated patients who underwent [68Ga]PSMA PET/MRI for staging or biopsy guidance, followed by radical prostatectomy at our institution between 07/2016 and 01/2020. The dominant lesion per patient was selected based on histopathology and correlated to PET/MRI in a multidisciplinary meeting, and quantified using SUVmax for PSMA uptake and ADCmean for diffusion restriction. PCa growth pattern was classified as expansive (EXP) or infiltrative (INF) according to its properties of forming a tumoral mass or infiltrating diffusely between benign glands by two independent pathologists. Furthermore, the corresponding WHO2016 ISUP tumor grade was evaluated. The t test was used to compare means, Pearson's test for categorical correlation, Cohen's kappa test for interrater agreement, and ROC curve to determine the best cutoff. RESULTS: Sixty-two patients were included (mean PSA 11.7 ± 12.5). The interrater agreement between both pathologists was almost perfect with κ = 0.81. While 25 lesions had an EXP-growth with an ADCmean of 0.777 ± 0.109, 37 showed an INF-growth with a significantly higher ADCmean of 1.079 ± 0.262 (p < 0.001). We also observed a significant difference regarding PSMA SUVmax for the EXP-growth (19.2 ± 10.9) versus the INF-growth (9.4 ± 6.2, p < 0.001). Within the lesions encompassing the EXP- or the INF-growth, no significant correlation between the ISUP groups and ADCmean could be observed (p = 0.982 and p = 0.861, respectively). CONCLUSION: PCa with INF-growth showed significantly lower SUVmax and higher ADCmean values compared to PCa with EXP-growth. Within the growth groups, ADCmean values were independent from ISUP grading.

Hot needles can confirm accurate lesion sampling intraoperatively using [18F]PSMA-1007 PET/CT-guided biopsy in patients with suspected prostate cancer.

PURPOSE: Prostate-specific membrane antigen (PSMA)-targeted PET is increasingly used for staging prostate cancer (PCa) with high accuracy to detect significant PCa (sigPCa). [68 Ga]PSMA-11 PET/MRI-guided biopsy showed promising results but also persisting limitation of sampling error, due to impaired image fusion. We aimed to assess the possibility of intraoperative quantification of [18F]PSMA-1007 PET/CT uptake in core biopsies as an instant confirmation for accurate lesion sampling. METHODS: In this IRB-approved, prospective, proof-of-concept study, we included five consecutive patients with suspected PCa. All underwent [18F]PSMA-1007 PET/CT scans followed by immediate PET/CT-guided and saturation template biopsy (3.1 ± 0.3 h after PET). The activity in biopsy cores was measured as counts per minute (cpm) in a gamma spectrometer. Pearson's test was used to correlate counts with histopathology (WHO/ISUP), tumor length, and membranous PSMA expression on immunohistochemistry (IHC). RESULTS: In 43 of 113 needles, PCa was present. The mean cpm was overall significantly higher in needles with PCa (263 ± 396 cpm) compared to needles without PCa (73 ± 44 cpm, p < 0.001). In one patient with moderate PSMA uptake (SUVmax 8.7), 13 out of 24 needles had increased counts (100-200 cpm) but only signs of inflammation and PSMA expression in benign glands on IHC. Excluding this case, ROC analysis resulted in an AUC of 0.81, with an optimal cut-off to confirm PCa at 75 cpm (sens/spec of 65.1%/87%). In all 4 patients with PCa, the first or second PSMA PET-guided needle was positive for sigPCa with high counts (156-2079 cpm). CONCLUSIONS: [18F]PSMA-1007 uptake in PCa can be used to confirm accurate lesion sampling of the dominant tumor intraoperatively. This technique could improve confidence in imaging-based biopsy guidance and reduce the need for saturation biopsy. TRIAL REGISTRATION NUMBER: NCT03187990, 15/06/2017.

What's behind 68Ga-PSMA-11 uptake in primary prostate cancer PET? Investigation of histopathological parameters and immunohistochemical PSMA expression patterns.

PURPOSE: Prostate-specific membrane antigen (PSMA-) PET has become a promising tool in staging and restaging of prostate carcinoma (PCa). However, specific primary tumour features might impact accuracy of PSMA-PET for PCa detection. We investigated histopathological parameters and immunohistochemical PSMA expression patterns on radical prostatectomy (RPE) specimens and correlated them to the corresponding 68Ga-PSMA-11-PET examinations. METHODS: RPE specimens of 62 patients with preoperative 68Ga-PSMA-11-PET between 2016 and 2018 were analysed. WHO/ISUP grade groups, growth pattern (expansive vs. infiltrative), tumour area and diameter as well as immunohistochemical PSMA heterogeneity, intensity and negative tumour area (PSMA%neg) were correlated with spatially corresponding SUVmax on 68Ga-PSMA-11-PET in a multidisciplinary analysis. RESULTS: All tumours showed medium to strong membranous (2-3 +) and weak to strong cytoplasmic (1-3 +) PSMA expression. Heterogeneously expressed PSMA was found in 38 cases (61%). Twenty-five cases (40%) showed at least 5% and up to 80% PSMA%neg. PSMA%neg, infiltrative growth pattern, smaller tumour area and diameter and WHO/ISUP grade group 2 significantly correlated with lower SUVmax values. A ROC curve analysis revealed 20% PSMA%neg as an optimal cutoff with the highest sensitivity and specificity (89% and 86%, AUC 0.923) for a negative PSMA-PET scan. A multiple logistic regression model revealed tumoural PSMA%neg (p < 0.01, OR = 9.629) and growth pattern (p = 0.0497, OR = 306.537) as significant predictors for a negative PSMA-PET scan. CONCLUSIONS: We describe PSMA%neg, infiltrative growth pattern, smaller tumour size and WHO/ISUP grade group 2 as parameters associated with a lower 68Ga-PSMA-11 uptake in prostate cancer. These findings can serve as fundament for future biopsy-based biomarker development to enable an individualized, tumour-adapted imaging approach.

Diagnostic performance of 68Ga-PSMA-11 PET/MRI-guided biopsy in patients with suspected prostate cancer: a prospective single-center study.

PURPOSE: Ultrasound-guided biopsy (US biopsy) with 10-12 cores has a suboptimal sensitivity for clinically significant prostate cancer (sigPCa). If US biopsy is negative, magnetic resonance imaging (MRI)-guided biopsy is recommended, despite a low specificity for lesions with score 3-5 on Prostate Imaging Reporting and Data System (PIRADS). Screening and biopsy guidance using an imaging modality with high accuracy could reduce the number of unnecessary biopsies, reducing side effects. The aim of this study was to assess the performance of positron emission tomography/MRI with 68Ga-labeled prostate-specific membrane antigen (PSMA-PET/MRI) to detect and localize primary sigPCa (ISUP grade group 3 and/or cancer core length ≥ 6 mm) and guide biopsy. METHODS: Prospective, open-label, single-center, non-randomized, diagnostic accuracy study including patients with suspected PCa by elevation of prostate-specific antigen (PSA) level and a suspicious lesion (PIRADS ≥3) on multiparametric MRI (mpMRI). Forty-two patients underwent PSMA-PET/MRI followed by both PSMA-PET/MRI-guided and section-based saturation template biopsy between May 2017 and February 2019. Primary outcome was the accuracy of PSMA-PET/MRI for biopsy guidance using section-based saturation template biopsy as the reference standard. RESULTS: SigPCa was found in 62% of the patients. Patient-based sensitivity, specificity, negative and positive predictive value, and accuracy for sigPCa were 96%, 81%, 93%, 89%, and 90%, respectively. One patient had PSMA-negative sigPCa. Eight of nine false-positive lesions corresponded to cancer on prostatectomy and one in six false-negative lesions was negative on prostatectomy. CONCLUSION: PSMA-PET/MRI has a high accuracy for detecting sigPCa and is a promising tool to select patients with suspicion of PCa for biopsy. TRIAL REGISTRATION: This trial was retrospectively registered under the name "Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) Guided Biopsy in Men with Elevated PSA" (NCT03187990) on 06/15/2017 ( https://clinicaltrials.gov/ct2/show/NCT03187990 ).

Improved detection of in-transit metastases of malignant melanoma with BSREM reconstruction in digital [18F]FDG PET/CT.

OBJECTIVES: To compare block sequential regularized expectation maximization (BSREM) and ordered subset expectation maximization (OSEM) for the detection of in-transit metastasis (ITM) of malignant melanoma in digital [18F]FDG PET/CT. METHODS: We retrospectively analyzed a cohort of 100 [18F]FDG PET/CT scans of melanoma patients with ITM, performed between May 2017 and January 2020. PET images were reconstructed with both OSEM and BSREM algorithms. SUVmax, target-to-background ratio (TBR), and metabolic tumor volume (MTV) were recorded for each ITM. Differences in PET parameters were analyzed with the Wilcoxon signed-rank test. Differences in image quality for different reconstructions were tested using the Man-Whitney U test. RESULTS: BSREM reconstruction led to the detection of 287 ITM (39% more than OSEM). PET parameters of ITM were significantly different between BSREM and OSEM reconstructions (p < 0.001). SUVmax and TBR were higher (76.5% and 77.7%, respectively) and MTV lower (49.5%) on BSREM. ITM missed with OSEM had significantly lower SUVmax (mean 2.03 vs. 3.84) and TBR (mean 1.18 vs. 2.22) and higher MTV (mean 2.92 vs. 1.01) on OSEM compared to BSREM (all p < 0.001). CONCLUSIONS: BSREM detects significantly more ITM than OSEM, owing to higher SUVmax, higher TBR, and less blurring. BSREM is particularly helpful in small and less avid lesions, which are more often missed with OSEM. KEY POINTS: • In melanoma patients, [18F]FDG PET/CT helps to detect in-transit metastases (ITM), and their detection is improved by using BSREM instead of OSEM reconstruction. • BSREM is particularly useful in small lesions.

Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach.

The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome-associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome-associated RCC exhibited an unusual morphology with accumulation of "colloid-like" cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next-generation sequencing analyses of HLRCC syndrome-associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC-RCC showed a second, undescribed NM_000143.3; c.947C>T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378+2T>C. In the other HLRCC syndrome-associated RCC, the FH mutation (NM_000143.3; c.462T>G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC - and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome-associated RCC, both cases were treated in first line with bevacizumab/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the "second hit" hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach.

68Ga-PSMA-11 PET has the potential to improve patient selection for extended pelvic lymph node dissection in intermediate to high-risk prostate cancer.

INTRODUCTION: Radical prostatectomy with extended pelvic lymph node dissection (ePLND) is a curative treatment option for patients with clinically significant localised prostate cancer. The decision to perform an ePLND can be challenging because the overall incidence of lymph node metastasis is relatively low and ePLND is not free of complications. Using current clinical nomograms to identify patients with nodal involvement, approximately 75-85% of ePLNDs performed are negative. The aim of this study was to assess the added value of 68Ga-PSMA-11 PET in predicting lymph node metastasis in men with intermediate- or high-risk prostate cancer. METHODS: 68Ga-PSMA-11 PET scans of 60 patients undergoing radical prostatectomy with ePLND were reviewed for qualitative (visual) assessment of suspicious nodes and assessment of quantitative parameters of the primary tumour in the prostate (SUVmax, total activity (PSMAtotal) and PSMA positive volume (PSMAvol)). Ability of quantitative PET parameters to predict nodal metastasis was assessed with receiver operating characteristics (ROC) analysis. A multivariable logistic regression model combining PSA, Gleason score, visual nodal status on PET and primary tumour PSMAtotal was built. Net benefit at each risk threshold was compared with five nomograms: MSKCC nomogram, Yale formula, Roach formula, Winter nomogram and Partin tables (2016). RESULTS: Overall, pathology of ePLND specimens revealed 31 pelvic metastatic lymph nodes in 12 patients. 68Ga-PSMA-11 PET visual analysis correctly detected suspicious nodes in 7 patients, yielding a sensitivity of 58% and a specificity of 98%. The area under the ROC curve for primary tumour SUVmax was 0.70, for PSMAtotal 0.76 and for PSMAvol 0.75. The optimal cut-off for nodal involvement was PSMAtotal > 49.1. The PET model including PSA, Gleason score and quantitative PET parameters had a persistently higher net benefit compared with all clinical nomograms. CONCLUSION: Our model combining PSA, Gleason score and visual lymph node analysis on 68Ga-PSMA-11 PET with PSMAtotal of the primary tumour showed a tendency to improve patient selection for ePLND over the currently used clinical nomograms. Although this result has to be validated, 68Ga-PSMA-11 PET showed the potential to reduce unnecessary surgical procedures in patients with intermediate- or high-risk prostate cancer.

Manual prostate cancer segmentation in MRI: interreader agreement and volumetric correlation with transperineal template core needle biopsy.

OBJECTIVES: To assess interreader agreement of manual prostate cancer lesion segmentation on multiparametric MR images (mpMRI). The secondary aim was to compare tumor volume estimates between MRI segmentation and transperineal template saturation core needle biopsy (TTSB). METHODS: We retrospectively reviewed patients who had undergone mpMRI of the prostate at our institution and who had received TTSB within 190 days of the examination. Seventy-eight cancer lesions with Gleason score of at least 3 + 4 = 7 were manually segmented in T2-weighted images by 3 radiologists and 1 medical student. Twenty lesions were also segmented in apparent diffusion coefficient (ADC) and dynamic contrast enhanced (DCE) series. First, 20 volumetric similarity scores were computed to quantify interreader agreement. Second, manually segmented cancer lesion volumes were compared with TTSB-derived estimates by Bland-Altman analysis and Wilcoxon testing. RESULTS: Interreader agreement across all readers was only moderate with mean T2 Dice score of 0.57 (95%CI 0.39-0.70), volumetric similarity coefficient of 0.74 (0.48-0.89), and Hausdorff distance of 5.23 mm (3.17-9.32 mm). Discrepancy of volume estimate between MRI and TTSB was increasing with tumor size. Discrepancy was significantly different between tumors with a Gleason score 3 + 4 vs. higher grade tumors (0.66 ml vs. 0.78 ml; p = 0.007). There were no significant differences between T2, ADC, and DCE segmentations. CONCLUSIONS: We found at best moderate interreader agreement of manual prostate cancer segmentation in mpMRI. Additionally, our study suggests a systematic discrepancy between the tumor volume estimate by MRI segmentation and TTSB core length, especially for large and high-grade tumors. KEY POINTS: • Manual prostate cancer segmentation in mpMRI shows moderate interreader agreement. • There are no significant differences between T2, ADC, and DCE segmentation agreements. • There is a systematic difference between volume estimates derived from biopsy and MRI.

Diagnostic Accuracy of Multiparametric MRI versus 68Ga-PSMA-11 PET/MRI for Extracapsular Extension and Seminal Vesicle Invasion in Patients with Prostate Cancer.

Background Recent studies have reported the additive value of combined gallium 68 (68Ga)-labeled Glu-urea-Lys (Ahx)-HBED-CC ligand targeting the prostate-specific membrane antigen (PSMA) (hereafter called 68Ga-PSMA-11) PET/MRI for the detection and localization of primary prostate cancer compared with multiparametric MRI. Purpose To compare the diagnostic accuracy and interrater agreement of multiparametric MRI and 68Ga-PSMA-11 PET/MRI for the detection of extracapsular extension (ECE) and seminal vesicle infiltration (SVI) in patients with prostate cancer. Materials and Methods Retrospective analysis of 40 consecutive men who underwent multiparametric MRI and 68Ga-PSMA-11 PET/MRI within 6 months for suspected prostate cancer followed by radical prostatectomy between April 2016 and July 2018. Four readers blinded to clinical and histopathologic findings rated the probability of ECE and SVI at multiparametric MRI and PET/MRI by using a five-point Likert-type scale. The prostatectomy specimen served as the reference standard. Accuracy was assessed with a multireader multicase analysis and by calculating reader-average areas under the receiver operating characteristics curve (AUCs), sensitivity, and specificity for ordinal and dichotomized data in a region-specific and patient-specific approach. Interrater agreement was assessed with the Fleiss multirater κ. Results For multiparametric MRI versus PET/MRI in ECE detection, respectively, AUC, sensitivity, and specificity in the region-specific analysis were 0.67 and 0.75 (P = .07), 28% (21 of 76) and 47% (36 of 76) (P = .09), and 94% (529 of 564) and 90% (509 of 564) (P = .007). For the patient-specific analysis, AUC, sensitivity, and specificity were 0.66 and 0.73 (P = .19), 46% (22 of 48) and 69% (33 of 48) (P = .04), and 75% (84 of 112) and 67% (75 of 112) (P = .19), respectively. For multiparametric MRI versus PET/MRI in SVI detection, respectively, AUC, sensitivity, and specificity of the region-specific analysis were 0.66 and 0.74 (P = .21), 35% (seven of 20) and 50% (10 of 20) (P = .25), and 98% (295 of 300) and 94% (282 of 300) (P < .001). For the patient-specific analysis, AUC, sensitivity, and specificity were 0.65 and 0.79 (P = .25), 35% (seven of 20) and 55% (11 of 20) (P = .20), and 98% (137 of 140) and 94% (131 of 140) (P = .07), respectively. Interrater reliability for multiparametric MRI versus PET/MRI did not differ for ECE (κ, 0.46 vs 0.40; P = .24) and SVI (κ, 0.23 vs 0.33; P = .39). Conclusion Our results suggest that gallium 68 (68Ga)-labeled Glu-urea-Lys (Ahx)-HBED-CC ligand targeting the prostate-specific membrane antigen (PSMA) (68Ga-PSMA-11) PET/MRI and multiparametric MRI perform similarly for local staging of prostate cancer in patients with intermediate-to-high-risk prostate cancer. The increased sensitivity of 68Ga-PSMA-11 PET/MRI for the detection of extracapsular disease comes at the cost of a slightly reduced specificity. © RSNA, 2019.

Extensive Histological Sampling following Focal Therapy of Clinically Significant Prostate Cancer with High Intensity Focused Ultrasound.

PURPOSE: Clinically significant, localized prostate cancer is currently treated with whole gland therapy. This approach is effective but associated with genitourinary and rectal side effects. Focal therapy of prostate cancer has been proposed as an alternative. The aim of this study was to determine the oncologic and functional outcomes of focal high intensity focused ultrasound therapy of prostate cancer. MATERIALS AND METHODS: In this single center, prospective study 75 men were treated between April 2014 and April 2018. Multiparametric magnetic resonance imaging and transperineal template saturation prostate biopsy were performed to localize prostate cancer, followed by focal ablation with high intensity focused ultrasound. The study primary end point was the detection of clinically significant prostate cancer, defined as Gleason score 7 or greater, at 6-month followup transperineal template saturation prostate biopsy. Genitourinary side effects were of secondary interest. RESULTS: Median patient age was 67 years (IQR 60-71) and median prostate specific antigen was 5.87 ng/ml (IQR 4.65-7.44). There were 5 low risk (6.7%) and 70 intermediate risk (93.3%) cancers. Clinically significant prostate cancer was detected in 41% of the men (95% CI 30.3-53.0) who underwent biopsy at 6 months and the median number of sampled cores was 44 (IQR 36-44). Prostate specific antigen (OR 1.17, IQR 0.49-2.85, p=0.71) and multiparametric magnetic resonance imaging (14.3% sensitivity, IQR 6.7-31.5) performed poorly to predict positive biopsies. Pad-free continence and erection sufficient for penetration were preserved in 63 of 64 (98.4%) and 31 of 45 patients (68.9%), respectively. CONCLUSIONS: Focal therapy with high intensity focused ultrasound leads to a low rate of genitourinary side effects. Followup biopsy of treated and untreated prostates remains the only modality to adequately select men in need of early salvage treatment.