Somatic Tumor Testing in Prostate Cancer: Experience of a Tertiary Care Center Including Pathologist-Driven Reflex Testing of Localized Tumors at Diagnosis.

Somatic tumor testing in prostate cancer (PCa) can guide treatment options by identifying clinically actionable variants in DNA damage repair genes, including acquired variants not detected using germline testing alone. Guidelines currently recommend performing somatic tumor testing in metastatic PCa, whereas there is no consensus on the role of testing in regional disease, and the optimal testing strategy is only evolving. This study evaluates the frequency, distribution, and pathologic correlates of somatic DNA damage repair mutations in metastatic and localized PCa following the implementation of pathologist-driven reflex testing at diagnosis. A cohort of 516 PCa samples were sequenced using a custom next-generation sequencing panel including homologous recombination repair and mismatch repair genes. Variants were classified based on the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists guidelines. In total, 183 (35.5%) patients had at least one variant, which is as follows: 72 of 516 (13.9%) patients had at least 1 tier I or tier II variant, whereas 111 of 516 (21.5%) patients had a tier III variant. Tier I/II variant(s) were identified in 27% (12/44) of metastatic biopsy samples and 13% (61/472) of primary samples. Overall, 12% (62/516) of patients had at least 1 tier I/II variant in a homologous recombination repair gene, whereas 2.9% (10/516) had at least 1 tier I/II variant in a mismatch repair gene. The presence of a tier I/II variant was not significantly associated with the grade group (GG) or presence of intraductal/cribriform carcinoma in the primary tumor. Among the 309 reflex-tested hormone-naive primary tumors, tier I/II variants were identified in 10% (31/309) of cases, which is as follows: 9.2% (9/98) GG2; 9% (9/100) GG3; 9.1% (4/44) GG4; and 13.4% (9/67) GG5 cases. Our findings confirm the use of somatic tumor testing in detecting variants of clinical significance in PCa and provide insights that can inform the design of testing strategies. Pathologist-initiated reflex testing streamlines the availability of the results for clinical decision-making; however, pathologic parameters such as GG and the presence of intraductal/cribriform carcinoma may not be reliable to guide patient selection.

Primary retroperitoneal lymph node dissection for metastatic non-seminomatous germ cell tumours: outcomes and adjuvant chemotherapy.

OBJECTIVES: To compare the outcomes and treatment burden of primary retroperitoneal lymph node dissection (pRPLND) alone versus pRPLND + adjuvant chemotherapy (AC) in patients with pathological stage II (PSII) non-seminomatous germ cell tumours (NSGCT). PATIENTS AND METHODS: Retrospective review of the Princess Margaret Cancer Center eTestes cancer database identified patients with PSII NSGCT after pRPLND between 1995 and 2020. The primary outcome was relapse-free survival (RFS). Secondary outcomes included disease-specific survival (DSS), burden of relapse treatment, and factors associated with relapse. RESULTS: A total of 109 PSII patients were included in the study. There were 96 patients treated with pRPLND alone and 13 treated with pRPLND + AC. The median follow-up was 61 months. The 5-year RFS was 72% for the pRPLND-only group vs 92% for the pRPLND + AC group (hazard ratio [HR] 4.372, 95% confidence interval [CI] 0.59-32.36; P = 0.11). Within the pRPLND-only group the 5-year RFS differed by pN stage (pN1 = 94% vs pN2/N3 = 67%, P = 0.03). Despite a higher relapse rate within the pRPLND-only group, the DSS was similar at 5 years (98% pRPLND only vs 100% pRPLND + AC, P = 0.48). Only 24 (25%) of the patients in the pRPLND-only group required any subsequent chemotherapy. Despite achieving similar survival, the cumulative post-RPLND treatment burden was less for the pRPLND-only group than the pRPLND+AC group overall (average 1.23 vs 2.46 cycles of chemotherapy per patient in group). CONCLUSION: The majority of patients with PSII NSGCT treated with pRPLND alone do not experience a recurrence or require chemotherapy. Despite a lower relapse risk when AC is given, no difference in survival was seen but higher chemotherapy burden was entertained. AC may constitute overtreatment for most patients with PSII NSGCT treated with pRPLND.

Metastatic solid tumours to the penis: a clinicopathologic evaluation of 109 cases from an international collaboration.

AIMS: To elucidate the spectrum of metastatic tumours to the penis and their clinicopathologic features. METHODS: The databases and files of 22 pathology departments from eight countries on three continents were queried to identify metastatic solid tumours of the penis and to characterize their clinical and pathologic features. RESULTS: We compiled a series of 109 cases of metastatic solid tumours that secondarily involved the penis. The mean patient age at diagnosis was 71 years (range, 7-94 years). Clinical presentation commonly included a penile nodule/mass (48/95; 51%) and localised pain (14/95; 15%). A prior history of malignancy was known in 92/104 (89%) patients. Diagnosis was made mainly on biopsy (82/109; 75%), or penectomy (21/109; 19%) specimens. The most common penile locations were the glans (45/98; 46%) and corpus cavernosum (39/98; 39%). The most frequent histologic type was adenocarcinoma (56%). Most primary carcinomas originated in the genitourinary (76/108; 70%) and gastrointestinal (20/108; 18%) tracts, including prostate (38/108; 35%), urinary bladder (27/108; 25%), and colon/rectum (18/108; 17%). Concurrent or prior extrapenile metastases were identified in 50/78 (64%) patients. Clinical follow-up (mean 22 months, range 0-171 months) was available for 87/109 (80%) patients, of whom 46 (53%) died of disease. CONCLUSION: This is the largest study to date of metastatic solid tumours secondarily involving the penis. The most frequent primaries originated from the genitourinary and gastrointestinal tracts. Metastatic penile tumours usually presented with penile nodules/masses and pain, and they often occurred in the setting of advanced metastatic disease, portending poor clinical outcomes.

Identification of intraductal carcinoma of the prostate on tissue specimens using Raman micro-spectroscopy: A diagnostic accuracy case-control study with multicohort validation.

BACKGROUND: Prostate cancer (PC) is the most frequently diagnosed cancer in North American men. Pathologists are in critical need of accurate biomarkers to characterize PC, particularly to confirm the presence of intraductal carcinoma of the prostate (IDC-P), an aggressive histopathological variant for which therapeutic options are now available. Our aim was to identify IDC-P with Raman micro-spectroscopy (RµS) and machine learning technology following a protocol suitable for routine clinical histopathology laboratories. METHODS AND FINDINGS: We used RµS to differentiate IDC-P from PC, as well as PC and IDC-P from benign tissue on formalin-fixed paraffin-embedded first-line radical prostatectomy specimens (embedded in tissue microarrays [TMAs]) from 483 patients treated in 3 Canadian institutions between 1993 and 2013. The main measures were the presence or absence of IDC-P and of PC, regardless of the clinical outcomes. The median age at radical prostatectomy was 62 years. Most of the specimens from the first cohort (Centre hospitalier de l'Université de Montréal) were of Gleason score 3 + 3 = 6 (51%) while most of the specimens from the 2 other cohorts (University Health Network and Centre hospitalier universitaire de Québec-Université Laval) were of Gleason score 3 + 4 = 7 (51% and 52%, respectively). Most of the 483 patients were pT2 stage (44%-69%), and pT3a (22%-49%) was more frequent than pT3b (9%-12%). To investigate the prostate tissue of each patient, 2 consecutive sections of each TMA block were cut. The first section was transferred onto a glass slide to perform immunohistochemistry with H&E counterstaining for cell identification. The second section was placed on an aluminum slide, dewaxed, and then used to acquire an average of 7 Raman spectra per specimen (between 4 and 24 Raman spectra, 4 acquisitions/TMA core). Raman spectra of each cell type were then analyzed to retrieve tissue-specific molecular information and to generate classification models using machine learning technology. Models were trained and cross-validated using data from 1 institution. Accuracy, sensitivity, and specificity were 87% ± 5%, 86% ± 6%, and 89% ± 8%, respectively, to differentiate PC from benign tissue, and 95% ± 2%, 96% ± 4%, and 94% ± 2%, respectively, to differentiate IDC-P from PC. The trained models were then tested on Raman spectra from 2 independent institutions, reaching accuracies, sensitivities, and specificities of 84% and 86%, 84% and 87%, and 81% and 82%, respectively, to diagnose PC, and of 85% and 91%, 85% and 88%, and 86% and 93%, respectively, for the identification of IDC-P. IDC-P could further be differentiated from high-grade prostatic intraepithelial neoplasia (HGPIN), a pre-malignant intraductal proliferation that can be mistaken as IDC-P, with accuracies, sensitivities, and specificities > 95% in both training and testing cohorts. As we used stringent criteria to diagnose IDC-P, the main limitation of our study is the exclusion of borderline, difficult-to-classify lesions from our datasets. CONCLUSIONS: In this study, we developed classification models for the analysis of RµS data to differentiate IDC-P, PC, and benign tissue, including HGPIN. RµS could be a next-generation histopathological technique used to reinforce the identification of high-risk PC patients and lead to more precise diagnosis of IDC-P.

Grading of prostate cancer: the impact of including intraductal carcinoma on the overall Grade Group assigned in diagnostic biopsies.

AIMS: The Gleason score/Grade Group (GrG) is a key parameter for clinical decision-making in prostate cancer. The World Health Organization currently recommends that intraductal carcinoma of the prostate (IDCP) should not be factored into the GrG; however, grading of IDCP is controversial, with variability among genitourinary pathologists. The aim of this study was to evaluate the impact of grading of the IDCP component on the final GrG in prostate biopsies. METHODS AND RESULTS: The study included 123 prostate biopsies (12 cores +/- additional MRI-targeted cores) with GrG1-GrG4 invasive carcinoma and IDCP. All cases were graded by a genitourinary pathologist using two different methods: (i) grading of invasive carcinoma only; and (ii) grading of both invasive carcinoma and IDCP. The overall GrG, excluding the IDCP component, was GrG1 in 3% (n = 4) of cases, GrG2 in 37% (n = 45), GrG3 in 52% (n = 64), and GrG4 in 8% (n = 10). When the IDCP component was included in grading, the overall GrG changed in 28 cases (23%). The GrG increased by one grade in 15 of 28 cases (54%), and by two or more grades in 13 of 28 cases (46%). Upgrading was due to comedonecrosis (39%, 11/28), solid growth (4%, 1/28), or an increased proportion of Gleason grade 4 (57%, 16/28). CONCLUSIONS: Although the GrG was unchanged in the majority of cases, grading of IDCP altered the final GrG in a significant minority of biopsies in this series, and often by more than one grade, which may have important implications for risk categorisation of individual patients. These findings highlight the need for consensus on grading of IDCP in routine practice, and the optimal method of incorporating IDCP into clinical risk models for patient management.

Handling and reporting of pelvic lymphadenectomy specimens in prostate and bladder cancer: a web-based survey by the European Network of Uropathology.

AIMS: Pathological evaluation of lymphadenectomy specimens plays a pivotal role in accurate lymph node (LN) staging. Guidelines standardising the gross handling and reporting of pelvic LN dissection (PLND) in prostate (PCa) and bladder (BCa) cancer are currently lacking. This study aimed to establish current practice patterns of PLND evaluation among pathologists. METHODS AND RESULTS: A web-based survey was circulated to all members of the European Network of Uropathology (ENUP), comprising 29 questions focusing on the macroscopic handling, LN enumeration and reporting of PLND in PCa and BCa. Two hundred and eighty responses were received from pathologists throughout 23 countries. Only LNs palpable at grossing were submitted by 58%, while 39% routinely embedded the entire specimen. Average LN yield from PLND was ≥10 LNs in 56% and <10 LNs in 44%. Serial section(s) and immunohistochemistry were routinely performed on LN blocks by 42% and <1% of respondents, respectively. To designate a LN microscopically, 91% required a capsule/subcapsular sinus. In pN+ cases, 72% reported the size of the largest metastatic deposit and 94% reported extranodal extension. Isolated tumour cells were interpreted as pN1 by 77%. Deposits identified in fat without associated lymphoid tissue were reported as tumour deposits (pN0) by 36% and replaced LNs (pN+) by 27%. LNs identified in periprostatic fat were included in the PLND LN count by 69%. CONCLUSION: This study highlights variations in practice with respect to the gross sampling and microscopic evaluation of PLND in urological malignancies. A consensus protocol may provide a framework for more consistent and standardised reporting of PLND specimens.

Role of Magnetic Resonance Imaging Targeted Biopsy in Detection of Prostate Cancer Harboring Adverse Pathological Features of Intraductal Carcinoma and Invasive Cribriform Carcinoma.

PURPOSE: The aim of this study was to compare biopsy detection of intraductal and cribriform pattern invasive prostate carcinoma in multiparametric magnetic resonance imaging positive and negative regions of the prostate. MATERIALS AND METHODS: We queried a prospectively maintained, single institution database to identify patients who underwent multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy and concurrent systematic sextant biopsy of magnetic resonance imaging negative regions between January 2013 and May 2016. All multiparametric magnetic resonance imaging targets were reviewed retrospectively by 2 readers for the PI-RADS™ (Prostate Imaging-Reporting and Data System), version 2 score, the maximum dimension, the apparent diffusion coefficient parameter and whether positive or negative on dynamic contrast enhancement sequence. Biopsy slides were reviewed by 2 urological pathologists for Gleason score/Grade Group and the presence or absence of an intraductal/cribriform pattern. RESULTS: A total of 154 patients were included in study. Multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy and systematic sextant biopsy of magnetic resonance imaging negative regions were negative for prostate carcinoma in 51 patients, leaving 103 available for the correlation of multiparametric magnetic resonance imaging and the intraductal/cribriform pattern. Prostate carcinoma was identified by multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy in 93 cases and by systematic sextant biopsy of magnetic resonance imaging negative regions in 76 (p = 0.008). Intraductal/cribriform positive tumor was detected in 23 cases, including at the multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy site in 22 and at the systematic sextant biopsy of magnetic resonance imaging negative region site in 3 (p <0.001). The intraductal/cribriform pattern was significantly associated with a PI-RADS score of 5 and a decreasing apparent diffusion coefficient value (p = 0.008 and 0.005, respectively). In 19 of the 23 cases with the intraductal/cribriform pattern prior 12-core standard systematic biopsy was negative in 8 and showed Grade Group 1 disease in 11. CONCLUSIONS: Multiparametric magnetic resonance imaging/ultrasound fusion targeted biopsy was associated with significantly increased detection of intraductal/cribriform positive prostate carcinoma compared to systematic sextant biopsy of multiparametric magnetic resonance imaging negative regions. This supports the role of magnetic resonance imaging to enhance the detection of clinically aggressive intraductal/cribriform positive prostate carcinoma.

Variant Histology and Clinicopathological Features of Prostate Cancer in Men Younger than 50 Years Treated with Radical Prostatectomy.

PURPOSE: While prostate cancer is primarily a disease of older men, young age prostate cancer represents an important clinical subgroup which has not been adequately studied. We evaluated the histopathological features and associated clinical behavior of prostate cancer in a cohort of younger men treated with radical prostatectomy. MATERIALS AND METHODS: The study included 171 men younger than 50 years with prostate cancer who were treated with radical prostatectomy at an academic institution between 2001 and 2015. Comprehensive pathology review was performed. Clinical and followup data were obtained from a prospectively maintained institutional database. RESULTS: Median age was 43 years (range 38 to 49). Of the tumors 42% were Gleason score 3 + 3 and 45% were 3 + 4 while Gleason score 4 + 3, 4 + 4 and 4 + 5 disease comprised 10.5%, 0.5% and 1% of cases, respectively. Mucinous carcinoma (greater than 25% extracellular mucin), an uncommon histological variant which comprises 0.2% of prostate cancers, was noted in 11 of our cases (6%). A further 21 cases (12%) of acinar adenocarcinoma had a less than 25% mucinous component. Followup data were available on 156 men (91%). Biochemical recurrence developed in 12 patients (19%) but there was no documented postoperative metastasis or death from disease in the cohort. All cases of mucinous carcinoma were associated with favorable clinicopathological characteristics. CONCLUSIONS: Our findings provide additional evidence that younger men with prostate cancer who are treated with radical prostatectomy mostly have favorable disease characteristics and outcomes. While the histopathological features in our series were generally comparable to those of older onset carcinoma, our cohort was enriched for tumors with a mucinous phenotype. Correlation with molecular-genetic analysis in this subset of tumors may be valuable.

Prostate carcinoma with amphicrine features: further refining the spectrum of neuroendocrine differentiation in tumours of primary prostatic origin?

AIMS: The current World Health Organization classification categorises high-grade neuroendocrine (NE) carcinomas of the prostate into small-cell and large-cell types. A distinct form of carcinoma showing synchronous dual exocrine and NE differentiation, termed amphicrine carcinoma, has been described at various other sites, primarily within the gastrointestinal tract. The aim of this study was to investigate the clinicopathological features of a series of metastatic prostate carcinoma (PCa) cases with amphicrine features. METHODS AND RESULTS: Five cases of high-grade PCa showing an amphicrine immunohistochemical phenotype were prospectively collected. The serum prostate-specific antigen (PSA) level at diagnosis ranged from 38 ng/ml to 992 ng/ml (median 200 ng/ml). All five patients had metastatic disease, four at initial presentation. Microscopically, the tumours showed a solid/nested growth pattern composed of cells with amphophilic cytoplasm, vesicular nuclei, and macronucleoli. Morphological features of small-cell or large-cell NE carcinoma were absent. As compared with conventional high-grade PCa, the tumour cells showed a higher level of nuclear pleomorphism, brisk mitotic activity, and a high Ki67 proliferation index (median 50%). All cases showed immunohistochemical positivity for PSA, androgen receptor, and prostate-specific acid phosphatase, combined with diffuse or confluent/non-focal positivity for chromogranin-A and synaptophysin. Two hormone-naive cases showed a clinical response to androgen deprivation therapy. CONCLUSION: This series highlights a previously undefined, clinically aggressive variant of PCa showing dual exocrine and NE differentiation, for which we are proposing the term PCa with amphicrine features. Increased recognition of these tumours may lead to a better understanding of their biology, and ultimately improve their clinical management.

Plaque inflammation and unstable morphology are associated with early stroke recurrence in symptomatic carotid stenosis.

BACKGROUND AND PURPOSE: Although symptomatic carotid stenosis is associated with 3-fold increased risk of early stroke recurrence, the pathophysiologic mechanisms of high early stroke risk have not been established. We aimed to investigate the relationship between early stroke recurrence after initial symptoms and histological features of plaque inflammation and instability in resected carotid plaque. METHODS: Carotid endarterectomy tissue from consecutive patients with ipsilateral stenosis≥50% and recent symptoms were analyzed using a validated histopathologic algorithm (Oxford Plaque Study [OPS] system). Nonprocedural stroke recurrence before carotid endarterectomy was ascertained at 7, 28, and 90 days after initial symptoms. RESULTS: Among 44 patients meeting eligibility criteria, 27.3% (12/44) had stroke recurrence after initial stroke/transient ischemic attack but before carotid endarterectomy. Compared with patients without recurrence, stroke recurrence was associated with dense macrophage infiltration (OPS grade≥3; 91.7% versus 37.5%; P=0.002), extensive (>25%) fibrous cap disruption (90.9% versus 37%; P=0.004), neovascularization (OPS grade≥2; 83.3% versus 43.8%; P=0.04), and low plaque fibrous content (OPS grade<2; 50% versus 6.3%; P=0.003). Early recurrence rates were 82.3% (confidence interval, 49.2%-98.8%) in patients with extensive plaque macrophage infiltration (OPS grade≥3) compared with 22.2% (confidence interval, 3.5%-83.4%) in those with OPS grade<3 (log-rank P=0.009). On multivariable Cox regression, including OPS macrophage grade (≥3 or <3), age, and severity of stenosis (50%-69% or ≥70%), plaque inflammation was the only variable independently predicting stroke recurrence (adjusted hazard ratio, 9; confidence interval, 1.1-70.6; P=0.04). CONCLUSIONS: Plaque inflammation and other vulnerability features were associated with highest risk of stroke recurrence and may represent therapeutic targets for future stroke prevention trials.

Frequency and clinicopathologic features of renal low-grade oncocytic tumour and eosinophilic vacuolated tumour: reclassification of 605 eosinophilic tumours including patients managed with active surveillance.

AIMS: Low-grade oncocytic tumour (LOT) and eosinophilic vacuolated tumour (EVT) are recently described emerging entities, which demonstrate distinct features but are not yet recognised as separate neoplasms in the fifth WHO classification. Published series to date have been largely multi-institutional and based on surgically resected tumours. This study aims to determine the frequency, clinicopathologic features and outcome of LOT and EVT in a single institutional series of oncocytic/eosinophilic renal neoplasms, including patients managed with active surveillance and non-surgical intervention. METHODS AND RESULTS: Cases were identified from a consecutive institutional series of in-house renal tumours diagnosed on biopsy and/or nephrectomy (2003-2023). Tumours with a diagnosis or differential diagnosis of oncocytoma, chromophobe renal cell carcinoma or oncocytic neoplasm not otherwise specified (including LOT, EVT and tumours with overlapping hybrid features) were retrospectively reviewed and classified/reclassified.In total, 605 oncocytic/eosinophilic renal neoplasms were reviewed, among which 33 LOT (5.5%) and 5 EVT (0.8%) were identified. LOT were CK7+, CD117- and GATA3+ (94%). EVT were CD117+, CK7 focal+ (80%) and cathepsin K+ (80%). At the median follow-up of 34 months (range 2-253) and 56 months (range 8-90) for LOT and EVT, respectively, there was no evidence of recurrence following ablation/surgical resection, metastasis or death from disease for all patients, including the 22 managed with active surveillance (20 LOT and 2 EVT). CONCLUSIONS: LOT and EVT comprised a minority of oncocytic renal neoplasms in this series. We report a large institutional series including patients managed non-surgically, with no adverse outcome, adding to the existing literature indicating a benign outcome.

Long-term Relapse and Survival in Clinical Stage I Testicular Teratoma.

BACKGROUND AND OBJECTIVE: Studies in metastatic nonseminomatous germ-cell tumor (NSGCT) suggest that the presence of teratomatous elements in the primary tumor is a risk factor for poor survival. Many guidelines have extrapolated this observation and recommend adjuvant retroperitoneal lymph-node dissection (RPLND) even for clinical stage I (CSI) teratoma confined to the testicle. Our objective was to assess relapse-free survival (RFS), cancer-specific survival (CSS), overall survival (OS) among patients with CSI pure teratoma in comparison to CSI NSGCT. METHODS: Patients with CSI NSGCT managed with surveillance between 1980 and 2023 were identified in the prospectively maintained Princess Margaret Cancer Centre database. We compared cases with pure teratoma with or without somatic transformation in the primary tumor to all other nonteratomatous NSGCTs. KEY FINDINGS AND LIMITATIONS: A total of 774 patients with CSI NSGCT were identified, including 63 (8.1%) with pure teratoma and/or somatic transformation in the primary tumor. Median follow-up was 61 mo. The pure teratoma group had superior RFS at 6 yr (85.2% vs 67.9%; p = 0.008). There were no significant differences in 6-yr CSS (100% vs 99.1%; p = 0.92) or OS (97.4% vs 98.1%; p = 0.33). Limitations include the single-center setting and the limited follow-up (median 61 mo), hindering the ability to detect late relapses. CONCLUSIONS AND CLINICAL IMPLICATIONS: CSI pure teratoma managed with surveillance is associated with a low risk of relapse overall and significantly lower risk of relapse in comparison to other CSI NSGCTs. No patients with CSI teratoma in the study population died of testicular cancer. Guidelines should be revised to include surveillance as a preferred approach for CSI teratoma. PATIENT SUMMARY: We compared survival rates after testicle removal in clinical stage I testicular cancer for two different tumor types. We found that cancer-specific and overall survival rates were similar for pure teratoma tumors and nonseminoma tumors, and that the recurrence rate was lower for pure teratoma tumors. Our results support surveillance as a suitable option after surgery for patients with clinical stage I testicular teratoma.

Metastatic solid tumors to the testis: a clinicopathologic evaluation of 157 cases from an international collaboration.

To elucidate the spectrum of metastatic solid tumors to the testis and their clinicopathologic features. The databases and files of 26 pathology departments from 9 countries on 3 continents were surveyed to identify metastatic solid tumors to the testis and to characterize their clinicopathologic features in detail. We compiled a series of 157 cases of metastatic solid tumors that secondarily involved the testis. The mean patient age at diagnosis was 64 years (range, 12-93 years). Most patients (127/144; 88%) had clinical manifestation of the disease, with testicular mass/nodule (89/127; 70%) being the most common finding. The main mechanism of testicular involvement was metastasis in 154/157 (98%) cases. Bilateral testicular involvement was present in 12/157 (8%) patients. Concurrent or prior extratesticular metastases were present in 78/101 (77%) patients. The diagnosis was made mainly in orchiectomy specimens (150/157; 95%). Different types of carcinomas (138/157; 87%), most commonly adenocarcinoma (72/157; 46%), were the most common malignancies. The most common primary carcinomas included prostatic (51/149; 34%), renal (29/149; 20%), and colorectal (13/149; 9%). Intratubular growth was identified in 13/124 (11%) cases and paratesticular involvement was found in 73/152 (48%) cases. In patients with available follow-up (110/157; 70%), more than half (58/110; 53%) died of disease. In this largest series compiled to date, we found that most secondary tumors of the testis represent metastases from the genitourinary and gastrointestinal tract carcinomas and typically occur in the setting of disseminated disease.

Dimensional reduction based on peak fitting of Raman micro spectroscopy data improves detection of prostate cancer in tissue specimens.

SIGNIFICANCE: Prostate cancer is the most common cancer among men. An accurate diagnosis of its severity at detection plays a major role in improving their survival. Recently, machine learning models using biomarkers identified from Raman micro-spectroscopy discriminated intraductal carcinoma of the prostate (IDC-P) from cancer tissue with a ≥85 % detection accuracy and differentiated high-grade prostatic intraepithelial neoplasia (HGPIN) from IDC-P with a ≥97.8 % accuracy. AIM: To improve the classification performance of machine learning models identifying different types of prostate cancer tissue using a new dimensional reduction technique. APPROACH: A radial basis function (RBF) kernel support vector machine (SVM) model was trained on Raman spectra of prostate tissue from a 272-patient cohort (Centre hospitalier de l'Université de Montréal, CHUM) and tested on two independent cohorts of 76 patients [University Health Network (UHN)] and 135 patients (Centre hospitalier universitaire de Québec-Université Laval, CHUQc-UL). Two types of engineered features were used. Individual intensity features, i.e., Raman signal intensity measured at particular wavelengths and novel Raman spectra fitted peak features consisting of peak heights and widths. RESULTS: Combining engineered features improved classification performance for the three aforementioned classification tasks. The improvements for IDC-P/cancer classification for the UHN and CHUQc-UL testing sets in accuracy, sensitivity, specificity, and area under the curve (AUC) are (numbers in parenthesis are associated with the CHUQc-UL testing set): +4 % (+8 % ), +7 % (+9 % ), +2 % (6%), +9 (+9) with respect to the current best models. Discrimination between HGPIN and IDC-P was also improved in both testing cohorts: +2.2 % (+1.7 % ), +4.5 % (+3.6 % ), +0 % (+0 % ), +2.3 (+0). While no global improvements were obtained for the normal versus cancer classification task [+0 % (-2 % ), +0 % (-3 % ), +2 % (-2 % ), +4 (+3)], the AUC was improved in both testing sets. CONCLUSIONS: Combining individual intensity features and novel Raman fitted peak features, improved the classification performance on two independent and multicenter testing sets in comparison to using only individual intensity features.

Optimal sampling of pelvic lymphadenectomy specimens following radical prostatectomy: is complete tissue submission justified?

There is currently no consensus among pathologists on the optimal method of sampling pelvic lympadenectomy specimens (PLND) in prostate cancer. We evaluated the impact of complete PLND submission on lymph node (LN) yield, detection of metastasis and laboratory workload in a series of 141 cases. Following isolation of grossly identifiable LNs/potential LNs, the remaining fatty tissue was embedded in toto. Complete PLND submission increased median LN yield from 10 (1-42) to 17 (3-57). Metastatic deposits were identified in nine non-palpable LNs, which altered the pN category in four cases (3%). The primary tumour (pT) was grade group ≥3 and/or pT3 at radical prostatectomy in 96% of pN+ cases. A median of seven additional blocks (1-28) was required for complete tissue embedding. Our findings indicate that submission of the entire fat can optimise PLND assessment but has a significant impact on laboratory workload. Complete submission of selected high-risk cases may be a reasonable alternative.

Accuracy of renal tumour biopsy for the diagnosis and subtyping of papillary renal cell carcinoma: analysis of paired biopsy and nephrectomy specimens with focus on discordant cases.

AIMS: Renal tumour biopsy (RTB) is increasingly recognised as a useful diagnostic tool in the management of small renal masses, particularly those that are incidentally found. Intratumoural heterogeneity with respect to morphology, grade and molecular features represents a frequently identified limitation to the use of RTB. While previous studies have evaluated pathological correlation between RTB and nephrectomy, no studies to date have focused specifically on the role of RTB for the diagnosis of papillary renal cell carcinoma (PRCC) and its further subclassification into clinically relevant subtypes. METHODS: This single-institution study evaluated 60 cases of PRCC for concordance between RTB and nephrectomy with respect to diagnosis, grading and subtyping (type 1/type 2). RESULTS: We observed 93% concordance (55 of 59 evaluable cases) between RTB and nephrectomy for the diagnosis of PRCC, although seven tumours (12%) were undergraded on RTB. Subtyping of PRCC on RTB was concordant with nephrectomy in 89% of cases reported as type 1 PRCC on RTB (31/35), but only 40% of cases reported as type 2 PRCC on RTB (4/10). Morphological misclassification of PRCC on RTB was most likely to occur in tumours showing a solid growth pattern. Discordant PRCC subtyping most often occurred in tumours with eosinophilia/oncocytic change. CONCLUSION: There was good concordance between RTB and nephrectomy for the primary diagnosis of PRCC. Although further subtyping of PRCC can aid therapeutic stratification, this can be challenging on RTB and tumours with overlapping or ambiguous features are best reported as PRCC not otherwise specified pending development of more robust methods to facilitate definitive subclassification.

Posttransplant Lymphoproliferative Disorders in Irish Renal Transplant Recipients: Insights From a National Observational Study.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) are a common malignancy after renal transplantation with a high incidence of PTLD described in the first posttransplant year. We sought to determine incidence and risk determinants of PTLD in Irish kidney transplant recipients. METHODS: Retrospective observational study of 1996 adult first kidney transplant recipients between 1991 and 2010 in the Republic of Ireland. Recipients were cross-referenced with the National Cancer Registry to determine incidence of PTLD. Kaplan-Meier analysis was performed for PTLD-free survival, allograft survival, and patient survival after PTLD. Cox proportional hazards models were used to identify independent risk factors for PTLD in our population. RESULTS: We identified 31 cases of PTLD during the study period. Histological subgroups included: early lesions (n = 1); polymorphic PTLD (n = 1); monomorphic PTLD (n = 27), Hodgkin disease (n = 2). Median time to PTLD diagnosis was 8.3 (range, 1.2-13.9) years. Cumulative incidence (95% CI) of PTLD at 1, 2, 3, 5, 10, and 15 years was 0%, 0.16% (0.05-0.5%), 0.21% (0.08-0.57%), 0.21% (0.08-0.57%), 1.76% (1.15-2.69%), and 3.07% (2.1-4.43%), respectively. Allograft survival after PTLD diagnosis was 94.4% (66.6-99.2%) at 5 years. Patient survival after PTLD diagnosis was 64% at 1 year, 53% at 2 years, 48% at 5 years, and 37% at 10 years. No risk factors for PTLD were identified. CONCLUSIONS: We found a paucity of early onset PTLD in our cohort with no cases in the first posttransplant year. Potential contributing factors included a high prevalence of previous Epstein-Barr virus exposure and a relatively low immunological risk profile in our recipient cohort compared with prior studies. Further studies are required to reevaluate the epidemiology of PTLD in the modern era of transplant immunosuppression.

Lymph node staging in prostate cancer: perspective for the pathologist.

Pelvic lymph node dissection (PLND) currently represents the gold standard method for nodal staging in the setting of localised prostate cancer and may also have a therapeutic benefit in certain patients. The histopathological evaluation of PLND specimens plays a critical role in accurate lymph node staging, however there is currently a lack of consensus regarding the optimum approach and no quality parameters are in place. In addition, there are no guidelines as to the handling of less commonly encountered nodal specimens such as those identified within the anterior fat pad. This summary provides an overview of pertinent issues regarding lymph node staging in prostate cancer, with a focus on the histopathological evaluation of resected nodal specimens. We hope that this review will further the discussion on how to achieve a more standardised approach to the processing and reporting of PLND specimens in the setting of prostate cancer.

Reflex Repeat HER2 Testing of Grade 3 Breast Carcinoma at Excision Using Immunohistochemistry and In Situ Analysis: Frequency of HER2 Discordance and Utility of Core Needle Biopsy Parameters to Refine Case Selection.

OBJECTIVES: The updated American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines (2013) for human epidermal growth factor receptor 2 (HER2) testing in breast cancer recommend repeat testing at excision of HER2-negative grade 3 breast tumors. This study aimed to identify the rate of HER2 discordance in this cohort of cases. METHODS: All HER2-negative grade 3 tumors diagnosed at a single institution over a 15-month period had reflex repeat HER2 testing at excision : HER2 testing was performed in accordance with ASCO/CAP guidelines using immunohistochemistry (IHC) and dual in situ hybridization (ISH). RESULTS: One hundred cases were identified over the study period. HER2 was amplified at excision in three cases. The discordant tumors showed equivocal IHC at excision with low-level amplification on dual ISH. All discordant cases showed equivocal IHC on core needle biopsy (CNB) specimens and/or tumor upgrade at excision. CONCLUSIONS: Our series demonstrated a high concordance rate (97%) for HER2 at excision in grade 3 breast tumors with a negative core biopsy result. These findings suggest that reflex repeat HER2 testing of all these cases, which has significant cost and workload implications, may not be justified. Features that may indicate HER2 heterogeneity, such as equivocal IHC on CNB specimens or tumor upgrade at excision, may help refine selection of cases for repeat testing.

Optimal Scoring of Brightfield Dual-Color In Situ Hybridization for Evaluation of HER2 Amplification in Breast Carcinoma: How Many Cells Are Enough?

OBJECTIVES: The purpose of this study was to determine the optimum number of cells that should be counted when scoring human epidermal growth factor receptor 2 (HER2) brightfield dual-color in situ hybridization (BDISH), including cases with HER2/chromosome 17 (Chr17) ratios in the 1.80 to 2.20 range. METHODS IN TOTAL,: 131 cases of breast carcinoma with HER2 immunohistochemistry and BDISH were included. For cases with a HER2/Chr17 ratio of less than 1.80 or more than 2.20 (n = 115), BDISH scoring was performed for 60 cells using three tumor fields, and for cases with a HER2/Chr17 ratio of 1.80 to 2.20 (n = 16), scoring was performed for 120 cells using six tumor fields. Mean HER2/Chr17 ratio and HER2 copy number were calculated for cumulative cell counts. RESULTS: The HER2 status as determined by the HER2/Chr17 ratio or HER2 copy number was unchanged following counting of additional cells in 100% of cases with ratio of less than 1.80 or more than 2.20. The HER2 status of two cases with ratios of 1.80 to 2.20 changed from positive to negative following counting of 120 cells. CONCLUSIONS: Our findings support recommendations to score 20 nuclei in conjunction with careful assessment of immunohistochemistry and scan of the BDISH slide to identify areas of heterogeneity. Scoring of additional cells/fields is likely not of benefit and might be a disadvantage since the scorer moves out of the area of strongest signal.