Accuracy of germ cell tumor histology and stage within a Canadian cancer registry.

INTRODUCTION: Cancer registries are the mainstay for Canadian population-based cancer statistics. Data are collected in provincial and territorial registries, including the Nova Scotia Cancer Registry (NS CR). The goal of this study was to determine the accuracy of NS CR data for germ cell tumors (GCT). METHODS: This analysis included all NS CR patients diagnosed with GCT from 2006-2015. The date and method of diagnosis, primary site, histology, and stage were recorded from the NS CR and compared to each patient's chart. Any discrepancies between the two sources were reviewed and reasons behind the discrepancies recorded. RESULTS: A total of 229 patients made up the study cohort. Using NS CR data, 57.6% had seminoma, 34.5% non-seminoma (NSG CT), and 7.9% other. Discrepancies in pathology were noted in 16 patients (7.0%). Using NS CR staging data (available in 185 cases), 71.9% had stage I, 12.4% stage II, 11.9% stage III, and 3.8% other. Discrepancies in stage were noted in 32 patients (17.3%) with NS CR data downstaging eight patients (4.3%) and upstaging 21 patients (11.4%). The site of the primary GCT was discrepant in 12 patients (5.2%). The date of diagnosis was accurate within one week for all patients except one. CONCLUSIONS: Higher-level NS CR data, such as date of diagnosis and overall pathological diagnosis, appear relatively accurate; however, there are inaccuracies in histological subtype and stage. This study raises awareness of these gaps and highlights key areas for improvement in educating registry personnel who interpret and enter data about the uniqueness of GCT pathology, staging, and interpretation of tumor markers.

Combined Transfer Learning and Test-Time Augmentation Improves Convolutional Neural Network-Based Semantic Segmentation of Prostate Cancer from Multi-Parametric MR Images.

PURPOSE: Multiparametric MRI (mp-MRI) is a widely used tool for diagnosing and staging prostate cancer. The purpose of this study was to evaluate whether transfer learning, unsupervised pre-training and test-time augmentation significantly improved the performance of a convolutional neural network (CNN) for pixel-by-pixel prediction of cancer vs. non-cancer using mp-MRI datasets. METHODS: 154 subjects undergoing mp-MRI were prospectively recruited, 16 of whom subsequently underwent radical prostatectomy. Logistic regression, random forest and CNN models were trained on mp-MRI data using histopathology as the gold standard. Transfer learning, unsupervised pre-training and test-time augmentation were used to boost CNN performance. Models were evaluated using Dice score and area under the receiver operating curve (AUROC) with leave-one-subject-out cross validation. Permutation feature importance testing was performed to evaluate the relative value of each MR contrast to CNN model performance. Statistical significance (p<0.05) was determined using the paired Wilcoxon signed rank test with Benjamini-Hochberg correction for multiple comparisons. RESULTS: Baseline CNN outperformed logistic regression and random forest models. Transfer learning and unsupervised pre-training did not significantly improve CNN performance over baseline; however, test-time augmentation resulted in significantly higher Dice scores over both baseline CNN and CNN plus either of transfer learning or unsupervised pre-training. The best performing model was CNN with transfer learning and test-time augmentation (Dice score of 0.59 and AUROC of 0.93). The most important contrast was apparent diffusion coefficient (ADC), followed by Ktrans and T2, although each contributed significantly to classifier performance. CONCLUSIONS: The addition of transfer learning and test-time augmentation resulted in significant improvement in CNN segmentation performance in a small set of prostate cancer mp-MRI data. Results suggest that these techniques may be more broadly useful for the optimization of deep learning algorithms applied to the problem of semantic segmentation in biomedical image datasets. However, further work is needed to improve the generalizability of the specific model presented herein.

Intraductal carcinoma of the prostate is an aggressive form of invasive carcinoma and should be graded.

Infiltration of the prostatic ducts by prostatic adenocarcinoma occurs relatively frequently, being most commonly associated with high grade disease. It is now recognised that intraductal carcinoma of the prostate (IDCP) has an associated poor prognosis and this is reflected in its histological, molecular and immunohistochemical features. The current recommendation of the World Health Organization is that IDCP not be taken into consideration when grading prostate adenocarcinoma. It is apparent that Gleason did not differentiate between IDCP and stromal invasive carcinoma when developing and validating his grading system, and recent studies suggest that the incorporation of IDCP grading into the overall grading of the specimen provides additional prognostic information.

Model-free prostate cancer segmentation from dynamic contrast-enhanced MRI with recurrent convolutional networks: A feasibility study.

Dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI) is a method of temporal imaging that is commonly used to aid in prostate cancer (PCa) diagnosis and staging. Typically, machine learning models designed for the segmentation and detection of PCa will use an engineered scalar image called Ktrans to summarize the information in the DCE time-series images. This work proposes a new model that amalgamates the U-net and the convGRU neural network architectures for the purpose of interpreting DCE time-series in a temporal and spatial basis for segmenting PCa in MR images. Ultimately, experiments show that the proposed model using the DCE time-series images can outperform a baseline U-net segmentation model using Ktrans. However, when other types of scalar MR images are considered by the models, no significant advantage is observed for the proposed model.

Spermatocytic Tumor With Sarcoma: A Rare Testicular Neoplasm.

Spermatocytic tumor, formerly known as spermatocytic seminoma, is an uncommon testicular neoplasm which is a distinct clinicopathologic entity from classic seminoma. These tumors are not associated with germ cell neoplasia in situ, other germ cell tumors, or isochromosome 12p. Although typically, these tumors have an excellent prognosis occasional cases are associated with sarcoma and have a very poor prognosis. We present a case of spermatocytic tumor with sarcoma showing a chondrosarcomatous component, discuss the pathologic findings and differential diagnosis and provide follow-up information.

Tumor-to-tumor metastases: papillary thyroid carcinoma into a clear cell renal cell carcinoma.

BACKGROUND: Thyroid metastases to distant sites are uncommon incidents, most often metastasizing to the lungs and bones. Rates of metastasis to the kidney are particularly low, ranging from 2.8-3.8% for papillary and 6-20% for follicular variants of well-differentiated thyroid cancers (WDTCs). In rare instances, tumor-to-tumor metastasis between two true primary neoplasms can occurs. This medical phenomenon has previously occurred as a clear cell renal cell carcinoma (CCRCC) spreading to a WDTC. To our knowledge, this is the first report of a tumor-to-tumor metastasis of a thyroid cancer metastasizing to a primary renal neoplasm. CASE PRESENTATION: A 72 year old male presented to the urology clinic with complaints of flank pain. Computed tomography (CT) imaging of the abdomen and pelvis revealed a 5.7 cm solid enhancing mass from the lateral aspect of the right kidney, suspicious for renal cell carcinoma (RCC). The patient subsequently underwent a right laparoscopic radical nephrectomy, and immunohistochemical staining of the 5.5 cm lesion revealed a positive RCC marker to establish a diagnosis of a pT1b ISUP Grade 2 CCRCC. The tumor contained a 3 mm focus of a lesion staining positive for TTF1 and Thyroglobulin, and negative for RCC marker. This finding established a diagnosis of a tumor-to-tumor metastasis of PTC to CCRCC. Subsequent ultrasound and CT of the head and neck revealed a heterogeneously hypodense 3.3 cm mass in the right thyroid lobe, prompting a total thyroidectomy and level VI neck dissection. Pathology revealed a classic variant multifocal PTC and two ipsilateral lymph nodes positive for metastatic PTC. Ultimately, the thyroid specimen was positive for lymphatic vascular invasion, extrathyroidal extension with invasion of the tracheal cartilage, staging as T4aN1aM1. On follow up examination the patient was recovering well, without signs of dysphagia or dysphonia, and showed bilateral mobile vocal cords on laryngoscope examination. CONCLUSIONS: Tumor-to-tumor metastasis between the thyroid and kidney is an extremely rare occurrence, reports of RCC metastases from a WDTC has not yet been reported in the literature. Corroboration of diagnostic imaging findings with immunohistochemistry staining can consolidate a diagnosis of thyroid neoplasm tumor-to-tumor metastasis to a RCC, thereby prompting surgical excision.

Accuracy of kidney cancer diagnosis and histological subtype within Canadian cancer registry data.

INTRODUCTION: Provincial/territorial cancer registries (PTCRs) are the mainstay for Canadian population-based cancer statistics. Each jurisdiction captures this data in a population-based registry, including the Nova Scotia Cancer Registry (NSCR). The goal of this study was to describe data from the NSCR regarding renal cell carcinoma (RCC) pathology subtype and method of diagnosis and compare it to the actual pathology reports to determine the accuracy of diagnosis and histological subtype assignment. METHODS: This retrospective analysis included patients diagnosed with RCC in the NSCR from 2006-2010 with an ICD-O-3 code C64.9 seen or treated in the largest NS health district. From the NSCR, method of diagnosis and pathological diagnosis was recorded. All diagnoses of non-clear-cell RCC (nonccRCC) from NSCR were compared to the actual pathology report for descriptive comparison and reasons for discordance. RESULTS: 723 patients make up the study cohort. 81.3% of patients were diagnosed by nephrectomy, 11.1% radiography, 6.9 % biopsy, and 0.7% autopsy. By NSCR data, 52.8% had clear-cell (ccRCC), 20.5% RCC not otherwise specified (NOS), 12.7% papillary, 4% chromophobe, and the rest had other nonccRCC subtypes. By pathology reports, 69.5% had clear-cell, 15% papillary, 5% chromophobe, only 2.7% RCC NOS. There was a discordance rate of 15.4% between NSCR data and diagnosis from pathology report. Reasons for discordance were not enough information by the pathologist in 45.5%, misinterpretation of report by data coder in 22.2%, and true coding error in 32.3%. CONCLUSIONS: When using PTCR for RCC incidence data, it is important to understand how the diagnosis is made, as not all are based on pathological confirmation; in this cohort 11% were based on radiology. One must also be aware that clear-cell and non-clear-cell subtypes may differ between the PTCR data and pathology reports. In this study, ccRCC made up 52.8% of the registry diagnoses, but increased to 69.6% on pathology report review. Use of synoptic reporting and ongoing education may improve accuracy of registry data.

Expression of OCT4 and SALL4 in Diffuse Large B-cell Lymphoma: An Analysis of 145 Consecutive Cases and Testicular Lymphomas.

OCT4 and SALL4 are transcription factors within a complex network that functions to maintain pluripotency in primitive stem cells and germ cells. Nuclear expression of OCT4 is widely cited as sensitive and specific for primary and metastatic germ cell tumors and is commonly used in the diagnosis of central nervous system (CNS) germinomas. Studies have failed to systematically examine the expression of OCT4 or SALL4 in diffuse large B-cell lymphoma (DLBCL), although this entity enters the morphologic differential diagnosis of some germ cell tumors. A retrospective review was conducted on 145 consecutive cases of DLBCL and testicular lymphoma to evaluate the prevalence of OCT4 and SALL4 expression. Nuclear OCT4 expression was present in 2/11 (18%) testicular DLBCLs and 6/134 (4.5%) nontesticular DLBCLs. Most OCT4 cases demonstrated moderate to strong expression in >50% of neoplastic cells. Rare, weak nuclear SALL4 expression was detected in only 3 nontesticular DLBCLs. Within the extratesticular DLBCL group, 2/6 (33%) primary CNS DLBCLs expressed nuclear OCT4. In addition, OCT4 DLBCL showed an overall predilection toward non-germinal center B-cell phenotype (7/8; 88%) and had a higher than expected rate of CD5 coexpression (4/8, 50%). These results are cautionary against using OCT4 as a sole marker of germ cell differentiation in testicular and extratesticular sites, especially in the CNS. The apparent associations of OCT4 expression with primary CNS DLBCL, non-germinal center B-cell phenotype, and CD5 coexpression raise the question of whether OCT4 expression in DLBCL may reflect more aggressive biology.

Paratesticular fibrous pseudotumour: Intraoperative frozen section analysis can help prevent unnecessary orchiectomy.

Paratesticular fibrous pseudotumours are rare intrascrotal lesions, most frequently affecting the testicular tunics. They are benign in nature; however, their pathogenesis is not completely understood. Presenting features are similar to testicular malignancy, which may result in unnecessary radical surgery. It has been suggested that additional diagnostic imaging combined with frozen section analysis may help prevent orchiectomy in these patients. We describe a case of paratesticular fibrous pseudotumour in a 40-year-old male treated with testicle-sparing surgery aided by intraoperative frozen section analysis.

Prolactin- and testosterone-induced carboxypeptidase-D correlates with increased nitrotyrosines and Ki67 in prostate cancer.

BACKGROUND: Carboxypeptidase-D (CPD) cleaves C-terminal arginine for conversion to nitric oxide (NO) by nitric oxide synthase (NOS). Prolactin (PRL) and androgens stimulate CPD gene transcription and expression, which increases intracellular production of NO to promote viability of prostate cancer (PCa) cells in vitro. The current study evaluated whether hormonal upregulation of CPD and NO promote PCa cell viabilty in vivo, by correlating changes in expression of CPD and nitrotyrosine residues (products of NO action) with proliferation marker Ki67 and associated proteins during PCa development and progression. METHODS: Fresh prostate tissues, obtained from 40 men with benign prostatic hyperplasia (BPH) or PCa, were flash-frozen at the time of surgery and used for RT-qPCR analysis of CPD, androgen receptor (AR), PRL receptor (PRLR), eNOS, and Ki67 levels. Archival paraffin-embedded tissues from 113 men with BPH or PCa were used for immunohistochemical (IHC) analysis of CPD, nitrotyrosines, phospho-Stat5 (for activated PRLR), AR, eNOS/iNOS, and Ki67. RESULTS: RT-qPCR and IHC analyses showed strong AR and PRLR expression in benign and malignant prostates. CPD mRNA levels increased ∼threefold in PCa compared to BPH, which corresponded to a twofold increase in Ki67 mRNA levels. IHC analysis showed a progressive increase in CPD from 11.4 ± 2.1% in benign to 21.8 ± 3.2% in low-grade (P = 0.007), 40.7 ± 4.0% in high-grade (P < 0.0001) and 50.0 ± 9.5% in castration-recurrent PCa (P < 0.0001). Immunostaining for nitrotyrosines and Ki67 mirrored these increases during PCa progression. CPD, nitrotyrosines, and Ki67 tended to co-localize, as did phospho-Stat5. CONCLUSIONS: CPD, nitrotyrosine, and Ki67 levels were higher in PCa than in benign and tended to co-localize, along with phospho-Stat5. The strong correlation in expression of these proteins in benign and malignant prostate tissues, combined with abundant AR and PRLR, supports in vitro evidence that the CPD-Arg-NO pathway is involved in the regulation of PCa cell proliferation. It further highlights a role for PRL in the development and progression of PCa.

Renal cell carcinoma after neuroblastoma: A case study and review of the literature.

We present a case of renal cell carcinoma (RCC) arising in a 26-year-old patient with a history of neuroblastoma. RCC after a previous diagnosis of neuroblastoma is very uncommon, and there have only been 23 reported cases. Using the results of our patient workup, we hoped to determine whether there was a genetic predisposition or iatrogenic cause for the RCC. There is no clear explanation why neuroblastoma survivors are prone to developing RCC. However, genetic predisposition and previous treatment likely play a role. Since there have been few cases described, and few investigations into the genetics of this subtype of RCC, it remains important for individual cases to be added to the literature of this recently described and rare entity.

A rare case of bladder chondroma.

Soft tissue chondromas are benign tumours that arise commonly in the hands and feet of adults, but rarely in other locations. Only two prior cases of chondroma of the urinary bladder wall have been reported. We describe a third case and discuss similarities and differences between the three cases reported to date.

Intraductal carcinoma of the prostate: interobserver reproducibility survey of 39 urologic pathologists.

The diagnosis of intraductal carcinoma (IDC) of the prostate remains subjective because 3 sets of diagnostic criteria are in use. An internet survey was compiled from 38 photomicrographs showing duct proliferations: 14 signed out as high-grade prostatic intraepithelial neoplasia (HGPIN), 17 IDC, and 7 invasive cribriform/ductal carcinoma. Each image was assessed for the presence of 9 histologic criteria ascribed to IDC. Thirty-nine respondents were asked to rate images as (1) benign/reactive, (2) HGPIN, (3) borderline between HGPIN and IDC, (4) IDC, or (5) invasive cribriform/ductal carcinoma. Intraclass correlation coefficient was 0.68. There was 70% overall agreement with HGPIN, 43% with IDC, and 73% with invasive carcinoma (P < .001, χ(2)). Respondents considered 19 (50%) of 38 cases as IDC candidates, of which 5 (26%) had a two-thirds consensus for IDC; two-thirds consensus for either borderline or IDC was reached in 9 (47%). Two-thirds consensus other than IDC was reached in the remaining 19 of 38 cases, with 15 supporting HGPIN and 4 supporting invasive carcinoma. Findings that differed across diagnostic categories were lumen-spanning neoplastic cells (P < .001), 2× benign duct diameters (P < .001), duct space contours (round, irregular, and branched) (P < .001), papillary growth (P = .048), dense cribriform or solid growth (both P = .023), and comedonecrosis (P = .015). When the 19 of 38 images that attained consensus for HGPIN or invasive carcinoma were removed from consideration, lack of IDC consensus was most often attributable to only loose cribriform growth (5/19), central nuclear maturation (5/19), or comedonecrosis (3/19). Of the 9 histologic criteria, only 1 retained significant correlation with a consensus diagnosis of IDC: the presence of solid areas (P = .038). One case that attained IDC consensus had less than 2× duct enlargement yet still had severe nuclear atypia and nucleomegaly. Six fold nuclear enlargement was not significant (P = .083), although no image had both 6× nuclei and papillary or loose cribriform growth: a combination postulated as sufficient criteria for IDC. Finally, 20.5% of respondents agreed that an isolated diagnosis of IDC on needle biopsy warrants definitive therapy, 20.5% disagreed, and 59.0% considered the decision to depend upon clinicopathologic variables. Although IDC diagnosis remains challenging, we propose these criteria: a lumen-spanning proliferation of neoplastic cells in preexisting ducts with a dense cribriform or partial solid growth pattern. Solid growth, in any part of the duct space, emerges as the most reproducible finding to rule in a diagnosis of IDC. Comedonecrosis is a rarer finding, but in most cases, it should rule in IDC. Duct space enlargement to greater than 2× the diameter of the largest, adjacent benign spaces is usually present in IDC, although there may be rare exceptions.

Carboxypeptidase-D is elevated in prostate cancer and its anti-apoptotic activity is abolished by combined androgen and prolactin receptor targeting.

BACKGROUND: Carboxypeptidase-D (CPD) cleaves C-terminal arginine for nitric oxide (NO) production. CPD and NO levels are upregulated by testosterone (T) and prolactin (PRL) to promote survival of prostate cancer (pCa) cells. This study evaluated CPD immunostaining and T/PRL regulation of CPD and NO levels in benign and malignant prostate tissues/cells to determine the role of CPD in pCa. METHODS: Immunohistochemistry (IHC) and tissue microarrays (TMA) were used to determine CPD immunostaining in prostate specimens. QPCR and immunoblotting were used to quantify CPD mRNA/protein expression in prostate cells. NO production was measured using 4,5-diaminofluorescein diacetate assay. RESULTS: CPD staining increased from 8.9 ± 3.8% (Mean ± SEM, n = 15) of benign epithelial cell area to 30.9 ± 2.9% (n = 30) of tumor cell area in one set of TMAs (P = 0.0008) and from 5.9 ± 0.9% (n = 45) of benign epithelial cell area to 18.8 ± 1.9% (n = 55) of tumor area in another (P < 0.0001). IHC of prostate tissues (≥50 mm(2)) confirmed increased CPD staining, from 13.1 ± 2.9% in benign (n = 16) to 29.5 ± 4.4% in pCa (n = 31, P = 0.0095). T and/or PRL increased CPD expression in several pCa but not benign cell lines. T and PRL acted synergistically to increase NO production, which was abolished only when receptor antagonists flutamide and Δ1-9-G129R-hPRL were used together. CONCLUSIONS: CPD immunostaining and T/PRL-stimulated CPD expression were higher in pCa than benign tissues/cells. Elevated CPD increased NO production, which was abolished when both AR and PRLR were inhibited. Our study implicates a critical role for the T/PRL-stimulated CPD-Arg-NO pathway in pCa progression, and suggests that AR+PRLR inhibition is a more effective treatment for pCa.

Metastatic renal cell carcinoma to the testis: A case report and review of the literature.

This is a case of a 68-year-old male who presented with a chief compliant of a testicular mass, which was discovered to be a meta-static lesion of undiagnosed renal cell carcinoma. A computed tomography scan revealed a large right renal mass and multiple pulmonary metastasis. Shortly after diagnosis, the patient was initiated on systemic therapy and received a cytoreductive nephrectomy. We discuss the details of this case as well as a pertinent review of metastatic renal cell carcinoma to the testes.

Intestinal type villous adenoma of the renal pelvis.

Intestinal type villous adenomas are uncommon in the genitourinary tract. Most reported cases have been located in the urinary bladder or urachus. Villous adenoma arising in the renal pelvis or ureter is very rare. We present a case of an 81-year-old female who presented with difficulty voiding and mucosuria. A computed tomography scan identified right-sided hydronephrosis, renal parenchymal atrophy, nonobstructing calculi and a lower pole renal mass. She underwent open right nephrectomy. Histopathologic examination of the kidney revealed an intestinal type villous adenoma of the renal pelvis with high-grade dysplasia and focal areas suspicious for invasive adenocarcinoma. We review the four previously reported cases of intestinal type villous adenoma in the renal pelvis and discuss diagnosis and management of this unusual neoplasm.

Preneoplasia in the prostate gland with emphasis on high grade prostatic intraepithelial neoplasia.

There are a variety of morphological patterns and processes that have been implicated in the pathogenesis of prostate cancer. Prostatic intraepithelial neoplasia (PIN), inflammation with or without atrophy, and adenosis (atypical adenomatous hyperplasia) have all been given candidate status as precursor lesions of prostatic adenocarcinoma. Based on decades of research, high grade prostatic intraepithelial neoplasia (HPIN), a proliferative lesion of prostatic secretory cells, has emerged as the most likely morphological pre-invasive lesion involved in the evolution of many but not all prostatic adenocarcinomas. In this manuscript, we briefly discuss other proposed precursors of prostatic adenocarcinoma and then focus on the history, diagnostic criteria and morphology of HPIN. The incidence of HPIN and its relationship to prostate cancer is reviewed. The differential diagnosis of large glandular patterns in the prostate is discussed in depth. Finally, we summarise the recent clinicopathological studies evaluating the clinical significance of HPIN and discuss follow-up strategies in men diagnosed with HPIN.

Adult granulosa cell tumor of the testicle.

We report a rare case of adult granulosa cell tumor of the testis in a 68-year-old man. A case and literature review of the associated clinical features, histopathological characteristics and immunochemistry are presented. The tumor is typically slow growing but has a higher risk of malignancy when > 5 cm. Our patient was disease-free 18 months following a right radical orchiectomy.

Clinical and pathologic factors of prognostic significance in penile squamous cell carcinoma in a North American population.

OBJECTIVE: To analyze, in a clinicopathologic correlation study, a small population of primarily white men with invasive squamous cell carcinoma of the penis for potential prognostic predictors. Penile squamous cell carcinoma is an uncommon cancer in North America. It has a wide spectrum of clinical behavior and an understudied pathogenesis. METHODS: The data from 43 patients with invasive squamous cell carcinoma of the penis were studied retrospectively. Extensive chart reviews were conducted, glass slides were reviewed, and tissue microarrays were constructed for analysis of immunohistochemical stains p16(INK4a), p53, and Ki-67. Univariate and multivariate logistic regression analyses were performed to elucidate any clinical or pathologic factors that would predict overall survival. RESULTS: The mean age at diagnosis was 63 years. Most cases (63%) were invasive squamous cell carcinoma, not otherwise specified, and presented as pathologic stage T1 or T2 tumors. Of the 43 patients, 23% died of their disease; 53% of the cases stained for p16(INK4a). Higher pathologic tumor stage and a lack of p16(INK4a) staining were independent predictors of worse overall survival (P = .014) and cancer-specific survival (P = .010). CONCLUSION: Our results have shown that 53% of the invasive penile squamous cell carcinoma cases in this population were associated with human papillomavirus, using p16(INK4a) as a surrogate marker of human papillomavirus infection. These patients had a statistically significant survival advantage, independent of other prognostic factors.