Cribriform Carcinoma Research Articles

Inter-observer variability of cribriform architecture and percent Gleason pattern 4 in prostate cancer: relation to clinical outcome

The Grade group is an important parameter for clinical decision-making in prostate cancer. Recently, percent Gleason pattern 4 and presence of invasive cribriform and/or intraductal carcinoma (CR/IDC) have been recognized for their independent predictive value for prostate cancer outcome. There is sparse data on the inter-observer agreement for these pathologic features in practice. Our objectives were to investigate inter-observer variability of percent Gleason pattern and CR/IDC and to relate individual tumour scores to clinical outcome. Our cohort included 80 consecutive radical prostatectomies with a median follow-up 87.1 months (interquartile range 43.3–119.2), of which the slide with largest tumour volume was scored by six pathologists for Grade group (four tiers: 1, 2, 3 and 4/5), percent Gleason pattern 4 (four tiers: 0–25%, 26–50%, 51–75% and 76–100%) and presence of CR/IDC (two tiers: absent, present). The individual assignments were related to post-operative biochemical recurrence (20/80). Inter-observer agreement was substantial (Krippendorff’s α 0.626) for assessment of Grade group and moderate for CR/IDC (α 0.507) and percent Gleason pattern 4 (α 0.551). For each individual pathologist, biochemical recurrence rates incremented by Grade group and presence of CR/IDC, although such relation was less clear for percent Gleason pattern 4. In conclusion, inter-observer agreement for CR/IDC and percent Gleason pattern 4 is lower than for Grade groups, indicating awareness of these features needs further improvement. Grade group and CR/IDC, but not percent Gleason pattern 4 was related to biochemical recurrence for each pathologist, indicating overall validity of individual grade assignments despite inter-observer variability.

Characteristics and prognosis of 17 special histologic subtypes of invasive breast cancers according to World Health Organization classification: comparative analysis to invasive carcinoma of no special type.

Breast cancer is a heterogeneous disease with various histopathologic subtypes. Except for invasive carcinoma of no special type (NST), other subtypes are rare with limited data. The purpose of this study was to analyze the characteristics and prognosis of special histopathologic subtypes of breast cancer compared to NST. A total of 136,140 patients were analyzed using the Korean Breast Cancer Society Registry database between January 1996 and March 2019. The clinicopathologic features and survival outcomes of special type breast carcinoma were compared with those of NST. The prevalence of special subtypes other than NST was 13.7% (n = 18,633). Compared to NST, patients with lobular, medullary, metaplastic, and micropapillary carcinoma had larger tumors (p < 0.001). Patients with mucinous, tubular, medullary, metaplastic, and cribriform carcinoma presented with less node metastasis (p < 0.001), contrary to patients with micropapillary carcinoma. Patients with lobular, mucinous, tubular, papillary, and cribriform carcinoma presented as luminal A subtype much more often (p < 0.001). Micropapillary carcinoma included more luminal B subtype (p < 0.001). Typically, medullary and metaplastic carcinoma included more triple-negative subtypes (p < 0.001). In survival analysis, only medullary (Hazard Ratio (HzR) 0.542, 95% CI 0.345 to 0.852, p = 0.008) and metaplastic carcinoma (HzR 1.655, 95% CI 1.317 to 2.080, p < 0.001) showed significantly different overall survival from NST by multivariate analysis. Breast cancer had distinct clinicopathologic features according to histopathologic subtype. However, special types of breast cancer had similar survival outcomes compared to NST when adjusting for other prognostic factors, except for metaplastic carcinoma and medullary carcinoma.

Aberrant integrin αv and α5 expression in prostate adenocarcinomas and bone-metastases is consistent with a bone-colonizing phenotype.

BackgroundCollaborative signaling between fibronectin-binding αv and α5 integrins has been implicated in the lethal dissemination of prostate cancer in the bone-metastatic niche, the major source of morbidity and mortality in the disease.MethodsWe assessed the frequency and pattern of expression of these integrins in primary high-grade adenocarcinomas and bone metastases compared to the physiological gland. Formalin-fixed paraffin-embedded (FFPE) radical prostatectomy (RP) samples (n=25) containing ≥ Gleason grade 4 cancer and decalcified surgical or diagnostic bone metastatic samples from 10 patients were stained for integrin αv (ITGAV) and integrin α5 (ITGA5) expression. Antibody optimization and antigen-retrieval was performed beforehand.ResultsITGAV was exclusively expressed in the basal layer of physiological prostate glands whereas αv expression was invariably recapitulated in the malignant gland and bone metastases (100%) in multiple distinct patterns: epithelial membranous, basilar/luminal membranous, punctate cytoplasmic, intense foci as single cells or clusters, and rim stromal layers. The luminal/basilar layer of ITGAV expression was striking in cribriform carcinomas, suggestive of a role in molecular pathogenesis. ITGA5 infrequently highlighted the basal layer of the physiological gland, was absent in primary adenocarcinoma, but was expressed with ITGAV exclusively in bone metastases (71%).ConclusionsWe conclude that ITGAV expression is aberrantly expressed in high frequency in high-grade prostatic adenocarcinomas in patterns suggestive of recapitulated basal cell functions, consistent with a stem-regulatory role that has been proposed. Co-expression and enrichment of αv and α5 in osseous metastases supports their proposed collaborative role in colonization of the bone microenvironment and as candidate targets for therapy.

Ophthalmopathologic characterization of multicentric or metastatic neoplasms with an extraocular origin in dogs and cats

To characterize the frequency and distribution of secondary ocular neoplasms in dogs and cats identified during necropsy. A retrospective analysis of necropsy records of dogs and cats was conducted, and cases with metastatic/multicentric neoplasms with an extraocular origin, involving the eyes, were selected. From January 2015 to January 2019, we identified a total of 233 dogs and 100 cats with metastatic disease. Of these, 11.6% (27/233) of the dogs and 13% (13/100) of the cats had ocular metastases. Lymphoma was the most common multicentric neoplasm involving the eyes of both species. In dogs, these neoplasms occurred bilaterally, predominantly in the anterior uvea, and were diffuse large B-cell, T-lymphoblastic, peripheral T-cell not otherwise specified, and lymphocytic B-cell lymphomas. In cats, feline leukemia virus (FeLV)-associated T-cell lymphoma was the most common. Mammary carcinoma was the second most common ocular metastatic neoplasm in bitches, with a predominantly unilateral involvement of the uveal tract. In cats, following lymphoma, pulmonary and squamous cell carcinomas were the most common multicentric/metastatic neoplasms of the eyes. Individual cases of cholangiocarcinoma, hemangiosarcoma, and chemodectoma in dogs, as well as mammary gland cribriform carcinoma, salivary gland carcinoma, and histiocytic sarcoma in cats were detected. The eyes of dogs were mostly affected by lymphoma or mammary gland carcinoma, while those of cats mostly had lymphoma, pulmonary carcinoma, or squamous cell carcinoma as the main metastatic/multicentric neoplasm. To the best of our knowledge, this is the first study to identify intraocular metastatic cholangiocarcinoma and chemodectoma in dogs, aside from identifying salivary gland carcinoma in cats.

The 2019 Genitourinary Pathology Society (GUPS) White Paper on Contemporary Grading of Prostate Cancer.

Controversies and uncertainty persist in prostate cancer grading. To update grading recommendations. Critical review of the literature along with pathology and clinician surveys. Percent Gleason pattern 4 (%GP4) is as follows: (1) report %GP4 in needle biopsy with Grade Groups (GrGp) 2 and 3, and in needle biopsy on other parts (jars) of lower grade in cases with at least 1 part showing Gleason score (GS) 4 + 4 = 8; and (2) report %GP4: less than 5% or less than 10% and 10% increments thereafter. Tertiary grade patterns are as follows: (1) replace "tertiary grade pattern" in radical prostatectomy (RP) with "minor tertiary pattern 5 (TP5)," and only use in RP with GrGp 2 or 3 with less than 5% Gleason pattern 5; and (2) minor TP5 is noted along with the GS, with the GrGp based on the GS. Global score and magnetic resonance imaging (MRI)-targeted biopsies are as follows: (1) when multiple undesignated cores are taken from a single MRI-targeted lesion, an overall grade for that lesion is given as if all the involved cores were one long core; and (2) if providing a global score, when different scores are found in the standard and the MRI-targeted biopsy, give a single global score (factoring both the systematic standard and the MRI-targeted positive cores). Grade Groups are as follows: (1) Grade Groups (GrGp) is the terminology adopted by major world organizations; and (2) retain GS 3 + 5 = 8 in GrGp 4. Cribriform carcinoma is as follows: (1) report the presence or absence of cribriform glands in biopsy and RP with Gleason pattern 4 carcinoma. Intraductal carcinoma (IDC-P) is as follows: (1) report IDC-P in biopsy and RP; (2) use criteria based on dense cribriform glands (>50% of the gland is composed of epithelium relative to luminal spaces) and/or solid nests and/or marked pleomorphism/necrosis; (3) it is not necessary to perform basal cell immunostains on biopsy and RP to identify IDC-P if the results would not change the overall (highest) GS/GrGp part per case; (4) do not include IDC-P in determining the final GS/GrGp on biopsy and/or RP; and (5) "atypical intraductal proliferation (AIP)" is preferred for an intraductal proliferation of prostatic secretory cells which shows a greater degree of architectural complexity and/or cytological atypia than typical high-grade prostatic intraepithelial neoplasia, yet falling short of the strict diagnostic threshold for IDC-P. Molecular testing is as follows: (1) Ki67 is not ready for routine clinical use; (2) additional studies of active surveillance cohorts are needed to establish the utility of PTEN in this setting; and (3) dedicated studies of RNA-based assays in active surveillance populations are needed to substantiate the utility of these expensive tests in this setting. Artificial intelligence and novel grading schema are as follows: (1) incorporating reactive stromal grade, percent GP4, minor tertiary GP5, and cribriform/intraductal carcinoma are not ready for adoption in current practice.

Pleomorphic lobular carcinoma in situ composed of signet ring cells mimicking cribriform ductal carcinoma in situ.

Pleomorphic lobular carcinoma in situ composed of signet ring cells mimicking cribriform ductal carcinoma in situ.

A Case of Cowden Syndrome with Bilateral Breast Cancer: Invasive Carcinoma of No Special Type and Pure Cribriform Carcinoma

: Cowden syndrome is an uncommon, multi-system disease that increases the risk of breast cancer. The most common breast malignancy is ductal carcinoma including ductal carcinoma in situ or infiltrating ductal carcinoma. Rare types of breast cancer exist, such as infiltrating tubular carcinoma and lobular carcinoma. There has been rarely a reported case of this type of breast cancer in Cowden syndrome. In this report, a 34-year-old woman diagnosed with Cowden syndrome underwent simple mastectomy for invasive carcinoma of no special type (NST) in the left breast, and simple mastectomy for cribriform carcinoma in the contralateral breast. Herein, we describe a case of Cowden syndrome with bilateral breast cancer, invasive carcinoma of NST in one breast and cribriform carcinoma in the contralateral breast.

Histological and molecular classification of breast cancer: what do we know?

Breast cancer is the neoplasm most diagnosed malignancy and the leading cause of mortality among women on a global scale. A profound increase in the understanding and clinical management of breast cancer has occurred over the past two decades, which has led to significant progress in prevention, early detection, and personalized breast cancer therapy. However, the biggest obstacle still faced in clinical practice is the complete understanding of intertumoral and intratumoral heterogeneity, in addition to the mechanisms of multiple drug resistance in the systemic treatment of the disease. In view of this, many studies focus on analyzing morphological and, mainly, molecular patterns of breast cancer, with the purpose of grouping these tumors into classes or entities to assist in clinical management, in the elaboration of epidemiological and functional studies, and in the performance of clinical trials. The most common special histological types of breast cancer include: medullary carcinoma, metaplastic carcinoma, apocrine carcinoma, mucinous carcinoma, cribriform carcinoma, tubular carcinoma, neuroendocrine carcinoma, classic lobular carcinoma, and pleomorphic lobular carcinoma, in addition to the non-specific type of invasive ductal carcinoma, which constitutes the majority of newly diagnosed cases. As to their molecular aspect, intrinsic subtypes were identified based on global studies of gene expression profiles. Today, four molecular subgroups are widely reproduced and well established in the clinical routine, namely: Luminal A, Luminal B, HER2 +, and Triple Negative. Thus, the present article aims to briefly address the histological and molecular classification of breast cancer.

Histological pattern of breast diseases in children and adolescents in North Central Nigeria

Background: Breast lesions are said to be rare and predominantly benign in the pediatric population. However, several case reports of malignant breast lesions in this demography exist, hence, the need to carefully examine breast masses when seen in children and adolescents to ascertain their nature. Aim: The aim of this study is to document the frequency, sex, and age distribution of the histologic subtypes of breast diseases seen in children and adolescents in a district hospital. Patients and Methods: Data were collated retrospectively from patients' request forms and duplicate copies of histology reports of all cases of breast lesions seen over a 5-year period at the pathology unit of Asokoro District hospital, Abuja, North Central Nigeria. Data were analyzed using Microsoft Excel, expressed using measures of central tendencies and percentages, and displayed using simple tables. Results: One-hundred and thirty-six cases of breast lesions were seen in the children and adolescent population (≤19 years), representing 16% of all the breast specimens during the study period. Females accounted for 97% with female-to-male ratio of 33:1. Their ages ranged from 10 to 19 years with modal age at presentation of 16 years. One (0.74%) case of invasive cribriform carcinoma was seen in a 17-year old boy. They presented as unilateral breast lesions in 88.6%, bilateral lesions in 9.6%, and unstated in 5.8% of patients, respectively. The most common lesion was fibroadenoma (74.3%), followed by fibrocystic change (10.3%). Conclusion: Breast lesions are common among older children and adolescents in our environment, mostly benign in nature and strikingly affect females. Fibroadenoma was the most common histologic lesion seen.

11P - The prognosis of rare histopathologic subtype of breast cancer

BackgroundBreast cancer is a heterogeneous disease with various histopathologic subtypes. As the prevalence of special types of breast cancer other than invasive carcinoma of no special type (NST) is low, limited data about the clinical behavior and prognosis according to the histologic types were documented with discordant results. The purpose of this study was to analyze the characteristics and the prognosis of rare histopathologic subtype of breast cancer compared with NST and to understand better for proper management. MethodsA total of 133,969 patients were analyzed in this study among the patients who were registered in the Korean Breast Cancer Society Registry database between January 1996 and March 2019 in Korea. ResultsThe prevalence of special types of breast cancer other than NST was 13.7% (n = 18,633). The patients with lobular, mucinous, tubular, papillary, and cribriform carcinoma presented as luminal A subtype much more than NST (77.6%, 74.6%, 77.2%, 57.4%, and 78.1% vs 47.5%, respectively, p < 0.001). A micropapillary carcinoma included more luminal B subtype with even high K-67 expression or positive HER2 than NST (40.9% vs 29.5%, p < 0.001). Typically, medullary and metaplastic carcinoma included more triple negative breast cancer (44.8% and 64.8% vs 13.5%, p < 0.001) than NST. In survival analysis, lobular (HR 0.879, p = 0.029), mucinous (HR 0.529, p < 0.001), tubular (HR 0.781, p < 0.001), papillary (HR 0.728, p < 0.001), medullary (HR 0.500, p < 0.001), and cribriform carcinoma (HR 0.291, p = 0.001) showed better overall survival than NST, and metaplastic carcinoma (HR 1.995, p < 0.001) showed worse outcome significantly. However, after adjusting for age, stage, molecular subtypes, grade, and lymphovascular invasion, only metaplastic carcinoma showed different overall (HR 1.762, p < 0.001) and breast cancer-specific survival (HR 1.685, p = 0.012) from NST. ConclusionsIn conclusion, invasive breast cancer had specific clinical and pathologic features according to the histopathologic subtype. However, special types of breast cancer other than NST have similar survival outcomes compared to NST when adjusting for other prognostic factors, except for metaplastic carcinoma. Editorial acknowledgementThis research was supported by the Korean Breast Cancer Society. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Evolution of prostate cancer histopathology.

During the last 15 years several updates in the Gleason grading have been made. With the help of pertinent research results pathologists have gained a better insight into the meanings of several prostate cancer (PCa) patterns and know better how to classify them in the Gleason grade system. During the last years PCa with cribriform architecture has be given much attention. Many data have also been published about the meaning of comedonecrosis and its relationship with Gleason pattern 4 and 5. The correlationship between comedonecrosis and intraductal PCa has also been highlighted in the recent literature. Intraductal PCa is one of the most described topics at the moment with implications to treatment such as radiation therapy. We also highlight several practical issues such as the differences of grading in prostate biopsies and prostatectomies and describe the problematic of reporting a minor high-grade pattern. Many new and recent data have allowed to refine diagnosis in PCa and improve the patients's treatment. We show that comedonecrosis can be overgraded and insist on the implication with cribriform and intraducatal carcinomas. Furthermore, we describe the importance of these PCa types especially in the consideration of further treatment.

Survival pattern of rare histological types of breast cancer in a Nigerian institution.

Introductionbreast cancer is the most common cancer affecting women worldwide. It is a heterogeneous disease with diverse histological types that are associated with different natural history and response to therapy. Invasive ductal and lobular carcinoma are the most common histological types. There are rare histological types with different biological behaviours from the common types, although treatment approaches are the same. Data on rare histological types of breast cancer in our population are scarce raising the need to identify these patients and document their treatment outcome. The objectives of this study are to determine the proportion and treatment outcomes of breast cancer patients with rare histological types.Methodsthis was an observational retrospective study using records of patients treated for breast cancer at the University College Hospital Ibadan Nigeria from 2008 to 2012. Patients with rare histological types were selected for further analysis. Data on patient and tumour characteristics were extracted and five-year survival pattern was determined using Kaplan Meier method.Resultsthe total number of patients with breast cancer was 761. Thirty-two (4.2%) had rare histology that consisted of medullary carcinoma 14(1.9%), mucinous carcinoma 10(1.4%) and 2(0.3%) each for squamous cell carcinoma, stromal sarcoma, cribriform carcinoma and Paget's disease. The overall five-year survival was 50% with median survival of 52 months.Conclusionthe proportion of breast cancer patients with rare histology is low similar to other reports among Caucasians. Medullary adenocarcinoma was the most common subtype followed by mucinous adenocarcinoma.

Gleason grade patterns in nodal metastasis and corresponding prostatectomy specimens: impact on patient outcome.

Lymph node metastases at the time of prostatectomy are an infrequent finding. The correlation of the pattern of nodal metastases with patient outcome has yet to be explored. Lymph node-positive prostatectomies were retrospectively reviewed. The presence of cribriform carcinoma (CC), intraductal carcinoma (IDC) and ISUP grade (G) were documented. The largest nodal metastasis was assessed for the morphological patterns present. G was assigned to the metastasis based on percentage morphological patterns present. Statistical analysis used spss to assess disease-specific survival (DSS), disease-free survival (DFS) and distant metastasis-free survival (DMFS). One hundred and ten cases were identified: G5 (n=52), G4 (n=8), G3 (n=34), G2 (n=10) and no G (n=6; treatment effect). IDC or CC was present in 103 (94%) specimens. More than one positive node correlated with worse DFS [P=0.012, hazard ratio (HR)=1.951, 95% confidence interval (CI)=1.142-3.331] and DMFS (P=0.009, HR=2.647, 95% CI=1.239-5.651). G in the prostate and nodal metastasis were poorly correlated (kappa=0.073, P=0.195). The presence of pattern 5 was seen in 33 nodes (30%) and correlated with DFS (P=0.020, HR=1.903, 95% CI=1.091-3.320), DSS (P=0.021, HR=5.937, 95% CI=1.084-32.533) and DMFS (P=0.007, HR=2.695, 95% CI=1.269-5.726). Nodal cribriform pattern showed no prognostic correlation and pattern 3 metastasis showed a significant trend towards better outcome (DMFS P=0.033, HR=0.431, 95% CI=0.194-0.958). IDC or CC is identified in 94% of node-positive prostate cancers. Although G in the largest nodal metastasis has prognostic significance, its G does not reflect that of the primary prostatic adenocarcinoma.

Improved Prostate Cancer Biopsy Grading by Incorporation of Invasive Cribriform and Intraductal Carcinoma in the 2014 Grade Groups

BackgroundGrade groups (GGs) are an important parameter for therapeutic decision making in prostate cancer (Pca) patients. Invasive cribriform and/or intraductal carcinoma (CR/IDC) has an independent prognostic value for disease outcome, but are not included in the GG limiting their clinical use. ObjectiveTo perform a proof-of-principle study incorporating CR/IDC in the current GG. Design, setting, and participantsAll prostate biopsies of 1031 men with screen-detected Pca between 1993 and 2000 were reviewed for the current GG (ranging from 1 to 5) and CR/IDC. The cribriform grade (cGrade) was equal to the GG if CR/IDC was present and GG minus 1 if not. GG1 was cGrade1 if intraductal carcinoma was absent. InterventionBiopsy review for GG and CR/IDC. A total of 406 patients had received radical prostatectomy (RP), 508 radiotherapy (RT), 108 surveillance, and eight hormonal therapy, and the treatment was unknown for one patient.Outcome measurements and statistical analysis disease-specific survival (DSS), metastasis-free survival (MFS), and biochemical recurrence–free survival (BCRFS) after 15.1 yr (interquartile range 10.9–19.7 yr) follow-up were compared using Harrell’s C-statistic. Results and limitationsThe biopsy GGs were 486 GG1, 310 GG2, 104 GG3, 64 GG4, and 67 GG5; cGrade distributions were 738 cGrade1, 102 cGrade2, 91 cGrade3, 58 cGrade4, and 42 cGrade5. The cGrade had a better discriminative value than the GG for DSS (C-index 0.79; 95% confidence interval 0.74–0.83 vs 0.76; 0.71–0.82) and MFS (0.79; 0.74–0.84 vs 0.77; 0.72–0.82). The discriminative value for BCRFS after RP and RT was similar for both models. Different diagnostic, such as use of sextant biopsies, and therapeutic strategies in the 1990s are the limitations of this study. ConclusionsThe cGrade is a simple Pca grade modification with better discriminative values for DSS and MFS than the GG, particularly impacting decision making in men with current GG2 Pca. Patient summaryMicroscopic grading is an important factor for decision making in prostate cancer (Pca) patients. We show that a simple grade modification better predicts Pca outcome and might improve treatment choices.

Concordance of cribriform architecture in matched prostate cancer biopsy and radical prostatectomy specimens.

AimsInvasive cribriform and/or intraductal carcinoma have been identified as independent adverse parameters for prostate cancer outcome. Little is known on biopsy undersampling of cribriform architecture. Our aim was to determine the extent of cribriform architecture undersampling and to find predictive factors for identifying false cribriform‐negative cases.Methods and resultsWe reviewed 186 matched prostate biopsies and radical prostatectomy specimens. Of 97 biopsy grade group 2 (Gleason score 3 + 4 = 7) patients, 22 (23%) had true cribriform‐negative (TN), 39 (40%) false‐negative (FN) and 36 (37%) true‐positive (TP) biopsies. Patients with FN biopsies had higher, although not statistically significant (P = 0.06), median PSA levels than patients with TP biopsies (12 versus 8 ng/ml). A PI‐RADS 5 lesion was present in nine of 16 (54%) FN and three of 11 (27%) TN biopsies (P = 0.05). Positive biopsy rate (P = 0.47), percentage Gleason pattern 4 (P = 0.55) and glomeruloid architecture (P = 1.0) were not different. Logistic regression identified PSA as an independent predictor (odds ratio = 3.5; 95% confidence interval = 1.2–9.4, P = 0.02) for cribriform architecture on radical prostatectomy, but not PI‐RADS score. The FN rate for large cribriform architecture at radical prostatectomy was 27%, which was lower than for any cribriform architecture (P = 0.01). During follow‐up (median 27 months), biochemical recurrence‐free survival of patients with TP biopsies was significantly shorter than that of those with FN biopsies (P = 0.03).ConclusionIn conclusion, 40% of grade group 2 prostate cancer biopsies were FN for cribriform architecture. These patients had higher PSA levels and more frequent PI‐RADS score 5 lesions than men with TN biopsies.

The molecular hallmarks and clinical consequences of tumor hypoxia in prostate cancer.

81 Background: Localised prostate cancers are classified into risk-groups using clinical measurements like grade and stage to inform treatment decisions. However, these groupings are imprecise: ~30% of intermediate-risk patients suffer relapse of their disease despite precision image-guided radiotherapy or radical prostatectomy. One reason for this variability in response to treatment is the underlying cellular and molecular heterogeneity of tumours. Prostate tumour cells exist within a microenvironment characterized by gradients of oxygen levels and prostate tumours with low levels of oxygen (hypoxia) have poor clinical outcomes. Methods: Hypoxia was measured using multiple mRNA-based signatures. We examined 548 patients with localised prostate cancer and statistically assessed the association of hypoxia with copy-number alterations (CNAs), single-nucleotide variants (SNVs), genomic rearrangements, focal genomic events ( i.e. kataegis, chromothripsis), telomere length, clinical indices ( i.e. grade, stage) and subclonal architecture. Results: Elevated hypoxia was associated with allelic loss of PTEN, higher rates of chromothripsis and intraductal and cribriform carcinoma (IDC-CA). To translate these findings into a biomarker for prostate cancer precision medicine, we integrated tumour microenvironmental data with genomic and pathological information to stratify patients into distinct prognostic groups. Patients with localized prostate cancer that have polyclonal tumours with elevated hypoxia, allelic loss of PTEN and IDC-CA were at the highest risk of rapid biochemical failure (P = 3.48 x10-3, Logrank test) and metastasis (P = 4.61 x 10-3, Logrank test), even after controlling for T-category, Gleason score and pre-treatment PSA. Conclusions: These data suggest that the aggressiveness of prostate cancers is driven by the interplay of the tumour microenvironment, tumour evolutionary trajectories and its genomic mutational profile.

Genetic and Epigenetic Determinants of Aggressiveness in Cribriform Carcinoma of the Prostate.

Among prostate cancers containing Gleason pattern 4, cribriform morphology is associated with unfavorable clinicopathologic factors, but its genetic features and association with long-term outcomes are incompletely understood. In this study, genetic, transcriptional, and epigenetic features of invasive cribriform carcinoma (ICC) tumors were compared with non-cribriform Gleason 4 (NC4) in The Cancer Genome Atlas (TCGA) cohort. ICC (n = 164) had distinctive molecular features when compared with NC4 (n = 102). These include: (i) increased somatic copy number variations (SCNV), specifically deletions at 6q, 8p and 10q, which encompassed PTEN and MAP3K7 losses and gains at 3q; (ii) increased SPOP mut and ATMmut ; (iii) enrichment for mTORC1 and MYC pathways by gene expression; and (iv) increased methylation of selected genes. In addition, when compared with the metastatic prostate cancer, ICC clustered more closely to metastatic prostate cancer than NC4. Validation in clinical cohorts and genomically annotated murine models confirmed the association with SPOPmut (n = 38) and PTENloss (n = 818). The association of ICC with lethal disease was evaluated in the Health Professionals Follow-up Study (HPFS) and Physicians' Health Study (PHS) prospective prostate cancer cohorts (median follow-up, 13.4 years; n = 818). Patients with ICC were more likely to develop lethal cancer [HR, 1.62; 95% confidence interval (CI), 1.05-2.49], independent from Gleason score (GS). IMPLICATIONS: ICC has a distinct molecular phenotype that resembles metastatic prostate cancer and is associated with progression to lethal disease.

Evolution, controversies and the future of prostate cancer grading.

Histological grading of prostate cancer is one of the most important tissue-based parameters for prediction of outcome and treatment response. Gleason grading remains the foundation of prostate cancer grading, but has undergone a series of changes in the past 30 years, often initiated by consensus conference decisions. This review summarizes the most important modifications that were introduced by the 2005 and 2014 International Society of Urological Pathology (ISUP) revisions of Gleason grading and discusses the impact that these have had on current grading practices. A considerable inflation in Gleason scores has been observed, especially following the ISUP 2005 revision, and the effects of this are discussed. ISUP 2014 grading recommendations are described, including the reporting of ISUP grades 1-5. Controversial issues include methods for reporting of grades on needle biopsies, reporting of percent Gleason grades 4/5 and grading of cribriform and intraductal carcinoma of the prostate. Educational programs developed recently to promote standardization of grading are described and their results assessed.

Large cribriform growth pattern identifies ISUP grade 2 prostate cancer at high risk for recurrence and metastasis

Invasive cribriform and intraductal carcinoma are associated with adverse clinical outcome in patients with Gleason score 7 prostate cancer. It is yet unclear whether invasive cribriform and intraductal carcinoma of the prostate both have independent prognostic value, or whether field size of invasive cribriform carcinoma has impact on disease outcome. Our objective was to determine the prognostic impact of intraductal and invasive cribriform prostate cancer histological subtypes in radical prostatectomies. We reviewed 420 prostatectomy specimens with ISUP grade 2 prostate cancer, assessed the percentages of Gleason grade 4 and tertiary 5, and performed immunohistochemistry for basal cells to discriminate intraductal from invasive cribriform growth. Small and large invasive cribriform fields were distinguished based on a diameter of at least twice the size of adjacent pre-existent normal glands. Clinicopathological parameters and biochemical recurrence-free survival were used as endpoints. Cribriform architecture was observed in 228 (54.3%) men, 103 (24.5%) of whom had intraductal, 194 (46.2%) small invasive, and 34 (8.1%) large invasive cribriform growth. Large invasive cribriform architecture was associated with older age (P < 0.001), higher percentage Gleason grade 4 (P = 0.001), extraprostatic expansion (P < 0.001), and more frequent lymph node metastases (P = 0.002), when compared with small invasive cribriform and/or intraductal carcinoma. Univariate analysis identified PSA, pT-stage, surgical margin status, and intraductal and invasive cribriform growth as significant predictors for biochemical recurrence-free survival. In multivariable Cox regression analysis, pT-stage (hazard ratio = 1.64, 95% CI: 1.02–2.63, P = 0.04), positive surgical margins (hazard ratio = 3.28, 95% CI: 2.06–5.23, P < 0.001), and large cribriform growth (hazard ratio = 4.36, 95% CI: 2.08–9.17, P < 0.001) were independent predictors for biochemical recurrence-free survival, while intraductal carcinoma, small cribriform growth, and percentage of Gleason grade 4 were not. In conclusion, large cribriform fields represent an aggressive subpattern of invasive cribriform prostate cancer and are an independent predictive factor for biochemical recurrence-free survival in ISUP grade 2 prostate cancer patients.

Her-2 expression in feline mammary lesions

Due to the high occurrence of mammary neoplasms in cats, the search for prognostic factors has recently intensified. Human epidermal growth factor receptor type 2 (Her-2) is prominent among the immunohistochemical markers used for prognosis. The aim of this study was to evaluate the expression of Her-2 in mammary lesions in queens and relate the expression to the type and histological grade of mammary carcinomas. Thirty-eight cases were selected from 2006 to 2016 and were classified and histologically graded. Her-2 expression was determined through immunohistochemistry, using a semi-quantitative analysis of the slides according to the scores recommended in the Dako HercepTest. Chi-square test was used to evaluate the relationship between Her-2 expression and mammary lesion type and the type and histological grade of carcinoma (P&lt; 0.05). The mean age was 8.5 years and young cats were affected only by benign hyperplasias and neoplasms. Undefined cats were more affected (84.37%), followed by Siamese (9.37%) and Persian (6.25%) cats. Regarding the histological classification, 18.42% of the mammary lesions were classified as hyperplasia, 18.42% as adenoma, and 63.16% as carcinoma. The most common type of carcinoma was tubulopapillary carcinoma (66.7%), followed by solid carcinoma (25%) and cribriform carcinoma (8.33%). Her-2 overexpression was observed in four samples (16.7%) of tubulopapillary carcinoma, two grade I carcinomas and two grade II carcinomas, but no relationship was observed between Her-2 expression and type of mammary lesion (P= 0.3127), carcinoma type (0.3446), or histological grade (0.6485). In conclusion, Her-2 overexpression is unrelated to histological grade and type.