Atypical Intraductal Proliferation Research Articles

Topline/Final Diagnostic Inclusion of Relevant Histologic Findings in Surgical Pathology Reporting of Carcinoma in Prostate Biopsies.

As the list of histologic parameters to include in surgical pathology reports of prostate cancer biopsies grows, some pathologists include this information in the microscopic description or summary sections of the report, whereas others include it in the "topline" or final diagnosis section. This prompted us to develop a multi-institutional survey to assess reporting trends among genitourinary (GU) pathologists. A survey instrument was shared among 110 GU pathologists via surveymonkey.com. Anonymized respondent data was analyzed. Eighty-four (76%) participants completed the survey across four continents. Most participants report tumor volume quantitation (88%), number of cores involved (89%), and both Gleason grade and Grade group (93%) in their topline; 71% include percent of pattern 4, with another 16% including it depending on cancer grade; 58% include the presence of cribriform growth pattern 4, with another 11% including it depending on cancer grade. When present, most include extraprostatic extension (90%), prostatic intraductal carcinoma (77%), and perineural invasion (77%). Inclusion of atypical intraductal proliferation (AIP) in the topline diagnosis was cancer grade-dependent, with 74% including AIP in Grade group 1, 61% in Grade group 2, 45% in Grade group 3, 30% in Grade group 4, and 26% in Grade group 5 cancers. Certain histologic features such as Gleason grade and tumor volume/cores involved are frequently included in the topline diagnosis, whereas the incorporation of other findings are more variably included. Prostate biopsy reporting remains a dynamic process with stylistic similarities and differences existing among GU pathologists.

Evaluating the use of vacuum-assisted excisions in the management of B3 breast lesions.

To evaluate the use of vacuum-assisted excisions (VAEs) in the management of B3 lesions within a single UK breast care centre. Assessment was made by determining the upgrade rates of the different B3 lesions at VAE. The study population comprised all patients who had a B3 result and subsequently underwent a VAE between November 2016 and October 2021. Patients with ipsilateral cancers were excluded. Retrospective biopsy and VAE results were reviewed. Upgrade rates and confidence intervals were calculated, and statistical significance was tested to determine any differences between upgrade rates of the B3 groups. 480 VAEs for B3 lesions were performed, with 10 excluded. Overall upgrade rate was 5%. 87.5% of upgrades were to non-invasive disease. Atypical intraductal epithelial proliferation (AIDEP) had a 15% upgrade rate, significantly different to lobular neoplasia (2%), papilloma without atypia (0%), and radial scar without atypia (0%). 10% of B3 lesions with atypia were upgraded, significantly different to 0% of B3 lesions without atypia. B3 lesions diagnosed by vacuum-assisted biopsy (VAB) had a significantly higher upgrade rate of 8% compared with 2% for lesions diagnosed by core biopsy (CBX), although this result was impacted by high numbers of AIDEP diagnosed by VAB. The results suggest using VAE for the management of AIDEP is appropriate. However, they also indicate that by performing VAEs of papillomas and radial scars without atypia, overtreatment may be occurring. This study adds to the ongoing discussion on the best treatment of B3 breast lesions.

WHO Classification of Tumours fifth edition: evolving issues in the classification, diagnosis, and prognostication of prostate cancer.

The fifth edition of the WHO Classification of Tumours of the Urinary and Male Genital Systems encompasses several updates to the classification and diagnosis of prostatic carcinoma as well as incorporating advancements in the assessment of its prognosis, including recent grading modifications. Some of the salient aspects include: (1) recognition that prostatic intraepithelial neoplasia (PIN)‐like carcinoma is not synonymous with a pattern of ductal carcinoma, but better classified as a subtype of acinar adenocarcinoma; (2) a specific section on treatment‐related neuroendocrine prostatic carcinoma in view of the tight correlation between androgen deprivation therapy and the development of prostatic carcinoma with neuroendocrine morphology, and the emerging data on lineage plasticity; (3) a terminology change of basal cell carcinoma to “adenoid cystic (basal cell) cell carcinoma” given the presence of an underlying MYB::NFIB gene fusion in many cases; (4) discussion of the current issues in the grading of acinar adenocarcinoma and the prognostic significance of cribriform growth patterns; and (5) more detailed coverage of intraductal carcinoma of prostate (IDC‐P) reflecting our increased knowledge of this entity, while recommending the descriptive term atypical intraductal proliferation (AIP) for lesions falling short of IDC‐P but containing more atypia than typically seen in high‐grade prostatic intraepithelial neoplasia (HGPIN). Lesions previously regarded as cribriform patterns of HGPIN are now included in the AIP category. This review discusses these developments, summarising the existing literature, as well as the emerging morphological and molecular data that underpins the classification and prognostication of prostatic carcinoma.

Cribriform Patterned Lesions in the Prostate Gland with Emphasis on Differential Diagnosis and Clinical Significance.

Simple SummaryA cribriform structure is defined as a continuous proliferation of cells with intermingled lumina. Various entities may have a cribriform morphology within the prostate gland, ranging from normal, to benign, to borderline and even to malignant lesions. This review summarizes the morphologic features of entities that have a cribriform morphology within the prostate gland, with an emphasis on their differential diagnosis, molecular profile and clinical significance. The basic aim is to assist the pathologist with challenging and controversial cases and inform the clinician on the clinical implications of cribriform morphology.Cribriform glandular formations are characterized by a continuous proliferation of cells with intermingled lumina and can constitute a major or minor part of physiologic (normal central zone glands), benign (clear cell cribriform hyperplasia and basal cell hyperplasia), premalignant (high-grade prostatic intraepithelial neoplasia), borderline (atypical intraductal cribriform proliferation) or clearly malignant (intraductal, acinar, ductal and basal cell carcinoma) lesions. Each displays a different clinical course and variability in clinical management and prognosis. The aim of this review is to summarize the current knowledge regarding the morphological features, differential diagnosis, molecular profile and clinical significance of the cribriform-patterned entities of the prostate gland. Areas of controversy regarding their management, i.e., the grading of Intaductal Carcinoma, will also be discussed. Understanding the distinct nature of each cribriform lesion leads to the correct diagnosis and ensures accuracy in clinical decision-making, prognosis prediction and personalized risk stratification of patients.

Rates and Outcomes of Breast Lesions of Uncertain Malignant Potential (B3) benchmarked against the National Breast Screening Pathology Audit; Improving Performance in a High Volume Screening Unit

IntroductionOur breast screening unit was identified as high outlier for B3 lesions with a low positive predictive value (PPV) compared to the England average. This prompted a detailed internal audit and review of B3 lesions and their outcomes to identify causes and address any variation in practice. Patients and MethodsThe B3 rate was calculated in 4168 breast core biopsies from 2019, using the subsequent excision to determine the PPV. Atypical intraductal epithelial proliferation (AIDEP) cases were subject to microscopic review to reassess the presence of atypia against published criteria. The B3 rate was re-audited in 2021, and the results compared. ResultsScreening cases had a high B3 rate of 12.4% (30% above the national average), and a PPV of 7.7% (9.7% with atypia). AIDEP was identified as a possible cause of this outlier status. On review and by consensus, AIDEP was confirmed in only 66% of cases reported as such, 17% were downgraded, and 16% did not reach consensus, the latter highlighting the difficulty and subjectivity in diagnosis of these lesions. Repeat audit of B3 rates after this extended review revealed a reduction from 12.4% to 9.11%, which is more in line with national standards. ConclusionBenchmarking against national reporting standards is critical for service improvement. Through a supportive environment, team working, rigorous internal review and adherence to guidelines, interobserver variation and outlier status in breast pathology screening outliers can both be addressed. This study can serve as a model to other outlier units to identify and tackle underlying causes.

Upgrade rates and outcomes of screen-detected atypical intraductal epithelial proliferation (AIDEP) diagnosed on core needle biopsy.

Atypical intraductal epithelial proliferation (AIDEP) is a breast lesion categorised as "indeterminate" if identified on core needle biopsy (CNB). The rate at which these lesions are upgraded following diagnostic excision varies in the literature. Women diagnosed with AIDEP are thought to be at increased risk of breast cancer. Our aim was to identify the rate of upgrade to invasive or in situ carcinoma in a group of patients diagnosed with AIDEP on screening mammography and to quantify their risk of subsequent breast cancer. We conducted a retrospective review of a prospectively maintained database containing all patients diagnosed with AIDEP on CNB between 2005 and 2012 in an Irish breast screening centre. Basic demographic data was collected along with details of the original CNB result, rate of upgrade to carcinoma and details of any subsequent cancer diagnoses. In total 113 patients were diagnosed with AIDEP on CNB during the study period. The upgrade rate on diagnostic excision was 28.3% (n =32). 6.2% (n =7) were upgraded to invasive cancer and 22.1% (n =25) to DCIS. 81 patients were not upgraded on diagnostic excision and were offered 5 years of annual mammographic surveillance. 9.88% (8/81) of these patients went on to receive a subsequent diagnosis of malignancy. The mean time to diagnosis of these subsequent cancers was 65.41 months (range 20.18-145.21). Our data showing an upgrade rate of 28% to carcinoma reflects recently published data and we believe it supports the continued practice of excising AIDEP to exclude co-existing carcinoma.

Role of vacuum assisted excision in minimising overtreatment of ductal atypias

PurposeB3 lesions are indeterminate lesions of uncertain malignant potential. They include lesions with and without epithelial atypia. Those with atypia include atypical intraductal epithelial proliferation (AIDEP)/atypical ductal hyperplasia (ADH) and flat epithelial atypia (FEA). They are traditionally managed with surgery. Vacuum assisted excision (VAE) allows larger samples to be obtained using a vacuum assisted biopsy (VAB) device, which equates to a surgical biopsy. We propose that VAE and mammographic surveillance is a safe alternative to surgery in managing the ductal atypias; (AIDEP/ADH and FEA). MethodRetrospective analysis of prospectively collected data on B3 lesions (April 2009 - March 2016) from consecutive breast screening patients diagnosed with AIDEP/ADH or FEA on initial diagnostic core biopsy. Mammographic abnormality, breast density, size, management pathway and upgrade to cancer and types of cancer were also collected during the treatment pathway and 5 year surveillance period (April 2009 - April 2019). Results273 cases of ductal atypia were identified. 187/273 (68.5 %) cases were managed with VAE only as no upgrade to malignancy and then 5 year mammographic surveillance. 34/273 (12.5 %) cases had a VAE diagnosing malignancy. 24/273 (8.8 %) cases had a VAE and then a surgical biopsy due to radiological or pathological concern, 8/24 upgraded to malignancy. 22/273 (8%) cases had a surgical diagnostic biopsy, 9/22 (41 %) cases were upgraded to malignancy.In total 51/273 (19 %) cases were diagnosed with cancer on the new pathway (13 invasive (all ER positive and Her2 negative) and 38 non-invasive, (34 ductal carcinoma in situ (DCIS) and 4 cases of lobular carcinoma in situ (LCIS)). While 17/273 (6.2 %) cases developed malignancy (12 invasive (all HER2 negative) and 4 DCIS and 1 LCIS) during the 5 year surveillance period. ConclusionsVAE is a safe alternative to surgery in managing ductal atypias. 187/273 (68.5 %) women avoided surgery. While 34/51 cancers (66.7 %) were diagnosed preoperatively using VAE, allowing the women to have a single therapeutic procedure.

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.

Mucinous lesions of the breast: potpourri of old and new

Mucinous lesions of the breast encompass a range of benign and malignant entities characterized by extracellular mucin production. Increased sampling of mammary calcifications has identified a range of mucocele-like lesions, which are associated with benign proliferative and atypical intraductal epithelial proliferation ranging in architectural complexity from flat epithelial atypia to ductal carcinoma in situ. Mucinous carcinoma is a unique histologic subtype of breast cancer with a good prognosis. Mucinous carcinoma, especially in males and older females, can arise in association with solid papillary carcinoma. Recent molecular studies reveal distinct genomic changes in mucinous carcinoma. Micropapillary mucinous carcinoma is a recently described histologic variant of breast cancer with aggressive clinical features and poorer outcome. Not all mucinous lesions are of ductal epithelial phenotype; rarely, lobular carcinoma can present with extracellular mucin. This concise review discusses clinical features, histological findings, and differential diagnoses of mucinous lesions of the breast, including common and some rare lesions as well as recently described entities.

Atypical intraductal proliferation detected in prostate needle biopsy is a marker of unsampled intraductal carcinoma and other adverse pathological features: a prospective clinicopathological study of 62 cases with emphasis on pathological outcomes.

Intraductal proliferations of the prostate with more complexity and/or cytological atypia than high-grade prostate intra-epithelial neoplasia (HGPIN), but falling short of intraductal carcinoma (IDC-P), are described as 'atypical intraductal proliferation' (AIP). When present in needle biopsy (NBX) without IDC-P, the clinical significance is not known. Sixty-two NBX cases were diagnosed as AIP over 7years with estimated incidence of 1%. AIP was characterised by loose cribriform architecture (90%) or non-cribriform architecture exhibiting significant nuclear atypia that fell short of IDC-P. Fifty patients had concomitant PCa (20% grade group (GG) 1, 48% GG2, 14% GG3, 8% GG4 and 10% GG 5), and 12 had AIP alone. Of 40 patients who were candidates for no therapy (AIP alone) or active surveillance (AIP with GG1 or GG2 PCa without cribriform pattern 4), 20 had subsequent follow-up pathology [seven NBXs and 13 radical prostatectomy (RP)]. Of the 12 AIP only patients, six had a subsequent biopsy diagnosis of: benign prostate (two), IDC-P with PCa (one) and PCa (three). One or more adverse pathological features at subsequent RP were present in 93% of patients with AIP and GG1 or GG2 PCa, defined as: GG ≥ 3(15%), IDC-P (77%), cribriform Gleason pattern 4 (69%), pT3a (77%) or pT3b (8%). AIP in NBX may be a marker of unsampled IDC-P and/or other adverse pathological features in suspected low- to intermediate-risk PCa. AIP should be considered distinct from HGPIN for risk assessment and warrant consideration for further work-up to detect unsampled high-risk PCa.

An audit of mammographic screen detected lesions of uncertain malignant potential (B3) diagnosed on initial image guided needle biopsy: how has our practice changed over 10 years?

To review all cases of B3 lesion diagnosed at initial image-guided needle biopsy over two 5-year cohorts to identify upgrade rates to malignancy and the effect of changing guidance on the management of such lesions. Data was collected retrospectively. Mammographic features, biopsy type and management were recorded for each lesion. Upgrade rates for each B3 histological category were quantified. Statistical analysis was performed using SPSS. There were 224 cases in 2005-2010 and 240 cases in 2010-2015. Mammographically 211 lesions were microcalcifications, 182 masses, 65 distortions and six asymmetric densities with no difference in the mammographic features in the two cohorts. Two hundred and eight 14 G core biopsies and 256 initial vacuum-assisted biopsies were performed. There was a statistically significant reduction in benign surgical biopsies and an increase in second-line vacuum biopsy/excision in the latter cohort, with no significant change in the upgrade rate. There was an overall 6% upgrade to invasive malignancy and 13% upgrade to ductal carcinoma in situ (DCIS). The upgrade rates for the following histological categories were atypical intraductal epithelial proliferation (AIDEP) 33.2% (21/63); classical (not pleomorphic) in situ lobular neoplasia (ISLN) 18.2% (6/33); flat epithelial hyperplasia (FEA) 21.7% (20/92); papilloma with atypia 53.8% (7/13), without atypia 12.1% (8/66); and radial scar/complex sclerosing lesion with atypia 16.7% (2/12), and without atypia 7.9% (6/76). Upgrade rates remain high for some histological categories even with first-line use of vacuum biopsy. Management of borderline lesions should be considered carefully in a multidisciplinary meeting. In many cases, the need for diagnostic surgical excision has been replaced by image-guided vacuum sampling.

Spectrum of Cribriform Proliferations of the Prostate: From Benign to Malignant.

- The presence of cribriform glands/ducts in the prostate can pose a diagnostic challenge. Cribriform glands/ducts include a spectrum of lesions, from benign to malignant, with vastly different clinical, prognostic, and treatment implications. - To highlight the diagnostic features of several entities with a common theme of cribriform architecture. We emphasize the importance of distinguishing among benign entities such as cribriform changes and premalignant to malignant entities such as high-grade prostatic intraepithelial neoplasia, atypical intraductal cribriform proliferation, intraductal carcinoma of the prostate, and invasive adenocarcinoma (acinar and ductal types). The diagnostic criteria, differential diagnosis, and clinical implications of these cribriform lesions are discussed. - Literature review of pertinent publications in PubMed up to calendar year 2017. Photomicrographs obtained from cases at the University of California at Irvine and authors' collections. - Although relatively uncommon compared with small acinar lesions (microacinar carcinoma and small gland carcinoma mimickers), large cribriform lesions are increasingly recognized and have become clinically and pathologically important. The spectrum of cribriform lesions includes benign, premalignant, and malignant lesions, and differentiating them can often be subtle and difficult. Intraductal carcinoma of the prostate in particular is independently associated with worse prognosis, and its presence in isolation should prompt definitive treatment. Patients with atypical intraductal cribriform proliferation, intraductal carcinoma of the prostate, or even focal cribriform pattern of invasive adenocarcinoma in biopsies would not be ideal candidates for active surveillance because of the high risk of adverse pathologic findings associated with these entities.

Endocrine mucin-producing sweat gland carcinoma: A study of 11 cases with molecular analysis.

Endocrine mucin-producing sweat gland carcinoma (EMPSGC) is a rare, low-grade adnexal neoplasm that most commonly involves the eyelid. Analogous to solid papillary carcinoma of the breast, it probably represents a precursor lesion to mucinous carcinoma. Here, we describe 11 cases of EMPSGC with molecular analysis. We performed a retrospective search of the Johns Hopkins Medical Institute pathology database and identified 11 cases of EMPSGC. Immunohistochemistry was performed for chromogranin, synaptophysin, neuron specific enolase, estrogen receptor (ER), epithelial membrane antigen (EMA), cytokeratin 7 (CK7), and cytokeratin 20 (CK20). Array comparative genomic hybridization (aCGH) and BRAFV600E pyrosequencing were performed on two and three cases, respectively. We observed a strong female predilection (73% females, 8/11 cases) with an average age of 66 years (range, 56-83 years). EMPSGCs were associated with adjacent benign sweat gland cysts (3/11), atypical intraductal proliferation (1/11), and mucinous carcinoma (1/11). Immunohistochemically, all tumors expressed at least one neuroendocrine marker, ER, EMA, and CK7, and were negative for CK20. aCGH demonstrated a 6p11.2 to 6q16.1 deletion (1/2 cases). All cases were negative for BRAFV600E mutation (3/3 cases). This series provides further histopathologic support that EMPSGC represents a multistage progression to mucinous carcinoma. Additional studies are needed to understand its molecular mechanisms.

Renaming Ductal Carcinoma in Situ: Would Removing “Carcinoma” Reduce Overtreatment?

In both the medical literature and lay press, a flurry of controversy has arisen surrounding the treatment and, more specifically, the potential overtreatment of ductal carcinoma in situ (DCIS). Since the advent of population-based screening mammography in the mid-1980s, the incidence of DCIS has increased more than 8-fold, with DCIS now accounting for nearly 22% of new breast cancer diagnoses.1,2 Since 1990, death rates from breast cancer in the United States have decreased by approximately 34%,1,3 a favorable outcome that has been attributed to the combination of increased screening mammography and improved adjuvant therapy.4 However, despite the steady increase in DCIS detection and treatment in the 1990s, the subsequent incidence of invasive breast cancers did not proportionately decrease.5 Invasive breast cancer incidence among women older than 50 years declined sharply between 2002 and 2003 but has since stabilized, a finding that could reflect a reduced pool of prevalent breast cancer cases as a result of widespread screening, but also could relate to the decreased use of hormone replacement therapy or trends in mammography screening rates that peaked in 2000.1 Approximately 1 in every 1300 screening mammography examinations leads to a diagnosis of DCIS, of which up to 30% will be treated with mastectomy.6,7 Several recent publications suggest the possibility that, although implementation of routine screening mammography has led to an overall increase in breast cancer detection and has been associated with a decrease in overall breast cancer mortality, it has not produced the magnitude of reduction in advanced-stage cancers one would expect based on detection of breast cancer at its nascent stage, namely DCIS.8 DCIS can be defined, to patients and providers alike, as noninvasive, preinvasive, a precursor to, stage 0, or, quite simply, what most patients hear at the end of such a preface: breast cancer. This dilemma in terminology has led to heated discourse at national breast specialty meetings and to front-page cover stories in The New York Times, and is an important issue to the growing constituency of breast cancer survivors who drive breast cancer awareness in this country.9 DCIS is a non–life-threatening, atypical intraductal proliferation that, if left untreated, can progress to invasive breast cancer. However, DCIS progression is not obligatory and not inevitable. Sanders et al10 showed that a significant fraction of DCIS cases will not progress to clinically apparent invasive disease. They examined the incidence of invasive breast cancer among a large cohort of patients originally diagnosed in the 1950s and 1960s as having benign breast pathology but who, on retrospective review were found to have low-grade DCIS. Of those with DCIS, only 40% subsequently developed an invasive breast cancer in the same quadrant of the same breast, most of which occurred within 10 years. Other studies, including population-based modeling experiments, have examined the natural history of low-grade DCIS and suggest that as few as 20% of cases might progress to invasive cancer over a protracted period spanning from 5 to 40 years.5 In the absence of progression to invasive cancer, overall survival after a diagnosis of DCIS is upwards of 98%. The goal of treatment is solely to prevent either local recurrence or progression to invasive breast cancer. Based on data from 4 randomized clinical trials, local treatment options for patients with DCIS currently include either breast-conserving surgery followed by radiation therapy, or mastectomy.11–14 Tamoxifen is also considered as possible adjuvant therapy for patients with estrogen receptor–positive DCIS, both for reduction of local recurrence risk after breastSara H. Javid, MD

Abstract LB-133: A novel tumor suppressor role for sirt1 inhibiting mitophagy in prostate mouse tissue.

Abstract Introduction. Sirtuin family consists of NAD+-dependent class III histone deacetylases (HDACs). Sirtuin family members (SIRT1-SIRT7) were shown to regulate a variety of physiopathological process, including aging, cellular proliferation, metabolism, and autophagy. Prior studies report SIRT1 as either an oncogene or a tumor suppressor depending upon the cell type and system. However, a reduced expression of SIRT1 in prostate cancer has been reported, supporting the view of SIRT1 as a tumor suppressor. Deregulated intracellular reactive oxygen species (ROS) production induces oxidative stress and damage of nucleic acids, proteins and lipids and may contribute to tumorigenesis. Herein, we provide in vivo support for SIRT1 as a tumor suppressor in prostate cancer. The mechanism appears to involve SIRT1-mediated inhibition of A) mitochondrial ROS production and B) mitophagy. Materials and methods. 7 month old Sirt1 transgenic mice were used. To investigate the molecular mechanisms through which SIRT1 regulate mitochondrial ROS production and mitophagy process, 3T3 cells wild type (Sirt1+/+) and SIRT1 knockout (Sirt1-/-) were used. Results. Our clinical and experimental data show a decrease in both SIRT1 expression associated with reduced patient survival probability. A histological evaluation of the H&E performed on both Sirt1+/+ and Sirt1-/- mouse prostate tissues demonstrates that there is a focal atypical intraductal proliferation in prostatic glands of the Sirt1-/- mice, compatible with high grade prostatic intraductal neoplasia (HGPIN). The IHC and relative quantitation of the mouse prostate tissues with Ki67 and AMACR, which are a proliferative and PIN marker respectively, showed an increase of both markers in Sirt1-/- mouse prostate tissue. Preliminary data generated from Sirt1+/+ and Sirt1-/- 3T3 cells suggest that SIRT has a key role in maintaining the mitochondrial healthy status regulating ROS. Sirt1-/- cells undergo a higher oxidative stress, which can lead to cellular damage. We also found mitophagy markers; Beclin1, Bnip3l and LC3 to be overexpressed in Sirt1-/- mouse prostate tissues. Conclusion and future prospects. These studies suggest SIRT1 inhibits PIN in vivo. The molecular mechanism through which SIRT1 works in a tumor suppressor way is still unknown. We propose a loss of SIRT1 expression may alter the oxidative environment, thereby promoting PIN. Citation Format: Gabriele Di Sante, Liping Wang, Chenguang Wang, Sara Bisetto, Mathew C Casimiro, Michael Powell, Michael McBurney, Richard Pestell. A novel tumor suppressor role for sirt1 inhibiting mitophagy in prostate mouse tissue. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-133. doi:10.1158/1538-7445.AM2013-LB-133

What is the significance of flat epithelial atypia and what are the management implications?

AimsTo assess the significance of flat epithelial atypia (FEA) on core biopsy by evaluating the proportion of cases upgraded to in-situ and invasive carcinoma on further sampling with vacuum-assisted biopsy...

Outcome of breast lesions diagnosed as lesion of uncertain malignant potential (B3) or suspicious of malignancy (B4) on needle core biopsy, including detailed review of epithelial atypia

To provide updated evidence of the outcome of breast lesions of uncertain malignant potential (B3) and suspicious of malignancy (B4) diagnosed on needle core biopsy (NCB) and analyse the outcome of the different types of intraductal epithelial atypia. One-hundred and forty-nine B3 and 26 B4 NCBs diagnosed over a 2-year period (2007-2008) were compared with those diagnosed over a previous 2-year period (1998-2000). The proportion of B3 diagnoses increased from 3.1% to 4.5%, and the positive predictive value (PPV) of malignancy of a B3 core decreased from 25% to 10%. Increased diagnosis of radial scar and reductions in the PPV of lobular neoplasia and of atypical intraductal proliferation may explain the reduction in the PPV of the B3 group as a whole. There were no significant changes in the proportion of B4 diagnosis (1.1% and 0.8%) or the PPV of B4 (83% and 88%). Review of cores with intraductal atypia showed a wide range of PPVs, from 100% for suspicious of ductal carcinoma in situ, to 40% for atypical ductal hyperplasia categorized as B3, and 14% for isolated flat epithelial atypia. The study has found a decrease in the PPV for a B3 diagnosis and suggests possible explanations.

Correlation of needle core biopsy with excision histology in screen-detected B3 lesions: the Merrion Breast Screening Unit experience

Aims:Needle core biopsy (NCB) is a widely-used technique for non-operative evaluation of screen-detected breast lesions. Although most NCBs are B2 (benign) or B5 (malignant), some fall into the B3 category...

Predictive value of needle core biopsy diagnoses of lesions of uncertain malignant potential (B3) in abnormalities detected by mammographic screening

Breast needle core biopsy (NCB) is now a commonplace diagnostic procedure in breast cancer screening, providing accurate diagnoses of both benign and malignant lesions. However, NCB may result in the borderline diagnoses of lesion of uncertain malignant potential (B3) or suspicious of malignancy (B4). The aim was to study a large series of B3 cases from population-based screening subjects in order to evaluate positive predictive values (PPVs) for malignancy. The results of 523 NCBs of women screened over a 7-year period (1999-2006) in the East Midlands region, UK, with a B3 diagnosis who underwent surgical excision, were reviewed and compared with the final excision histology. Five percent of NCBs were reported as B3. The most frequent histological subtypes were atypical intraductal epithelial proliferation (AIDEP) and radial scar/complex sclerosing lesion (RS/CSL). Final excision histology was benign in 417 (80%) and malignant in 106 (20%) subjects (60 ductal carcinoma in situ and 46 invasive carcinoma). Lesion-specific PPVs were as follows: AIDEP 32%; lobular neoplasia (LN) 30%; RS/CSL with AIDEP or LN 24%; RS/CSL without atypia 9%; papillary lesion with AIDEP or LN 36%; and papillary lesion without atypia 4%. Five of the 32 fibroepithelial lesions with cellular stroma were phyllodes tumours (four benign and one borderline). None of the five mucinous lesions on NCB was malignant. Our results show that approximately one-fifth of NCB of screen-detected breast lesions classified as B3 are malignant on excision, and the likelihood of malignancy varies substantially between different histological subtypes.

Will the spectrum of lesions prompting a “B3” breast core biopsy increase the benign biopsy rate?

Aim: To audit the benign surgical biopsies in women screened, assessed, and referred by the Leeds/Wakefield Breast Screening Unit for the year 1999–2000 with a view to determining any association...