Nonproliferative Lesions Research Articles

Classic Lesions of the Biliary Tree.

Abnormal findings in the biliary tree are frequently encountered in response to acute and chronic exposures to various compounds. The more common findings are described here in an overview of previous publications such as the INHAND Proliferative and Nonproliferative Lesions of the Rodent Liver and the Liver-Nonneoplastic Lesion Atlas NTP with comments regarding current considerations. This was presented at the 2023 Annual Meeting of the Society of Toxicologic Pathology. Histologic descriptions and some discussions regarding the pathogenesis of the various categories of non-neoplastic lesions in the biliary tree are presented. Discussions regarding the use of the term oval cell versus ductular reaction and the potentially neoplastic nature of cholangiofibrosis are presented in some detail.

Abstract 3587: High resolution microCT to analyze the 3D morphology of microcalcifications in benign breast disease and breast cancer biopsy tissues

Abstract Introduction: We used micro-computed tomography (microCT), a high-resolution imaging option, to detect and characterize microcalcifications (MCs) in three dimensions within pathology blocks of benign and malignant breast tissues. Methods: A set of 44 formalin-fixed, paraffin-embedded breast tissue blocks were assessed from n=22 women at two time points: benign breast biopsy and subsequent DCIS or DCIS with invasive disease breast cancer. Blocks were scanned using the Bruker Skyscan 1276 microCT at a resolution of 10 µm. SkyScan analysis CTAn software was utilized to prepare and analyze morphological parameters and multiple MCs contained within each block were averaged. Paired morphological parameters were compared between the benign and subsequent cancer samples within women using Wilcoxon signed-rank tests. Results: Median age of patients was 53 years (range 37-77 years) at initial benign biopsy and developed breast cancer at median of 5.6 years (range: 2.3-12.8 years) later. The initial benign biopsies were for proliferative disease without atypia in the majority (59%), while 23% had non-proliferative lesions and 18% atypical hyperplasia. The average structural model index was consistent with a near rod-like shape (median 2.99, range: 2.71-3.29). Paired comparisons between benign and cancer blocks showed that the average surface area of MCs was significantly higher in the cancer samples (p=0.0467), as was the average volume of MCs (p=0.0298) (Table 1). Conclusions: Preliminarily, we demonstrate that microCT of routinely prepared pathology blocks of breast tissues may be useful in characterizing the 3-D morphometry of MCs with suggestive differences in benign and cancer tissues. Given that MCs are a sentinel radiologic marker of DCIS but are common in benign breast disease, developing improved approaches for classifying MCs may have value in breast cancer screening and management. Table 1. Comparison of MC parameters in biopsy tissues (IQR = Interquartile Range). Benign sample from women who later developed breast cancer Breast cancer after prior benign sample Paired Differences (Cancer - Benign) Wilcoxon signed-rank p value (N=22) (N=22) (N=22) Number of Objects (Median (IQR)) 43.5 (14, 789) 69.5 (33, 289) -6 (-139, 67) 0.6830 Average Surface Area (mm2)(Median (IQR)) 0.0225 (0.0134, 0.0393) 0.0342 (0.0185, 0.0656) 0.0113 (-0.0027, 0.0322) 0.0467 Average Volume (mm3) (Median (IQR)) 0.0003 (0.0001, 0.0007) 0.0007 (0.0003, 0.0022) 0.0003 (0.000002, 0.0020) 0.0298 Average Surface Area/Volume (mm−1)(Median (IQR)) 214.92 (162.25, 328.39) 199.55 (151.89, 230.52) -20.85 (-86.05, 27.04) 0.1433 Average Structural Thickness (mm)(Median (IQR)) 0.0341(0.0196, 0.0446) 0.0395 (0.0336, 0.0505) 0.0074 (-0.0062, 0.0153) 0.1173 Average Structural Model Index (Median (IQR)) 2.9758 (2.8465, 3.1175) 3.0026 (2.9281, 3.0927) 0.0075 (-0.1073, 0.1381) 0.7656 Citation Format: Sarah E. Schrup, Thomas de Bel, Tanya Hoskin, Teresa Allers, Stacey Winham, Derek Radisky, Laura Pacheco-Spann, Lisa Seymour, Amy Degnim, Mark Sherman. High resolution microCT to analyze the 3D morphology of microcalcifications in benign breast disease and breast cancer biopsy tissues. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3587.

Identify Breast Cancer Risk Factors Using the Gail Assessment Model in Iraq.

The prevalence of breast cancer (BC) has increased significantly in the last 50 years worldwide. This increase may be because more women today have mammograms and, as a result, are more known to have cancers. At the same time, the theory is growing that many other factors contribute to the increase in cancer rates. The current study tried applying the Gail assessment model to identify hormonal and familial risk factors that may be important for BC in Iraq. Patients aged 30 years and over with all known risk factors for BC were selected for the study group. The selected patients were divided into two groups. Group 1: Patients diagnosed with non-proliferative lesions who have had a breast biopsy performed at least three years before; Group 2: Controlled patients. The individual risk of BC for patients in groups 1 and 2 was calculated using the Gale model. In addition to groups 1 and 2, we identified two other groups. Group 3: Groups 1 and 2 of patients without BC at the end of the 3-year follow-up period; Group 4: Patients who have undergone BC surgery. Multiple regression tests assessed all known risk factors in groups 3 and 4 to determine the risk factors for the development of BC in Iraq. The results show that Gail's assessment model is a reliable example of calculating the risk of developing BC. The model results show that the significant risk factor for BC in Iraq is not hormonal but genetic or familial. Current research also shows that the risk of developing BC increases significantly with age. It was concluded that there are genetic factors, and the risk of developing BC increases with age, but hormonal features do not cause a significant increase in risk. Identifying risk factors in causing disease in the community makes it possible to prepare codified plans to control and treat the disease.

Clinical and Pathological Features of Bovine Ischaemic Teat Necrosis

Bovine ischaemic teat necrosis (ITN) is an emerging disease of unknown aetiology affecting mostly dairy cows in the early stages of first lactation and a substantial welfare concern frequently leading to premature culling and economic losses. Specific diagnostic criteria are lacking. The aims of this study were to develop an appropriate ITN grading system, describe the histopathological changes and investigate the potential aetiological role of several pathogens in 47 cows with 73 ITN lesions from 28 farms. ITN lesions were allocated to one of three broad macroscopic categories: presence of a non-proliferative lesion on the teat (type 1); proliferative teat lesion with crusting (type 2); severe purulent to eosinophilic, ulcerative and necrotising dermatitis and sloughing or total absence of the teat (type 3). Lesions were mostly observed on the medial aspect of the teat but there was no anatomical predisposition as to which teats were more frequently affected. In approximately 50% of the ITN teats reviewed, the lesions were continuous with the skin of the udder and 34.2% of cases had sloughed or partially sloughed teats. The main histological findings were: focally extensive severe purulent to eosinophilic, ulcerative and necrotizing dermatitis; serocellular crust formation; and epidermal hyperplasia with dyskeratosis. Some lesions also had leucocytoclastic to eosinophilic vasculitis and thrombosis with ischaemic necrosis. Macroscopic and histological analyses confirmed the suspected ischaemic nature of the lesions but the specific aetiopathogenesis was elusive with a wide range of bacteria present, probably as opportunistic infections. However, Treponema spp and Orthopox virus were excluded as major aetiological agents. This study establishes a foundation for further investigations of the pathogenesis of bovine ITN and a basis for consistency in diagnosis and classification of the stage of disease. The findings are also key to further understanding disease progression and prognosis.

Dermatophilosis in ruminants and horses in the southern region of Rio Grande do Sul between 2009-2019

This study has the objective of describing the epidemiology of dermatophilosis in cattle, horse, and sheep in the southern of Rio Grande do Sul during a period of 10 years. Data was gathered of all cases/outbreaks of dermatophilosis in ruminants and equines There were 44 (49,4%) diagnoses of dermatophilosis out of 89 cases presenting non-proliferative cutaneous lesions. Of these, 13 were in cattle, 29 in horses, and two were in sheep. It was made a consultation to the Hospital de Clínicas of Porto Alegre/RS and DATASUS database to determine the occurrence of dermatophilosis in humans due to its zoonotic characteristic. It was observed that both in public hospitals and in the SUS database, dermatopathies are recorded in a non-specific way, and with dermatophilosis being a dermatopathy with nonspecific lesions, the definitive diagnosis with the characterization of the agent is not made. The results of this study allowed to conclude that dermatophilosis has a relative importance in domestic species since mortality not occurs in cattle and horses. Still, one must consider the lower dairy production in cattle. In sheep, there was mortality and losses due to the fall in wool quality, and the disease should be considered in diagnosing skin lesions in this species. In humans, the disease is underreported and the possibility of its occurrence in rural areas is alerted; however, cases rarely reach the laboratory.

Efficacy of Modified Masood Scoring System (MMSS) in Cytological Diagnosis of Breast Lesions.

Introduction: Fine-needle aspiration cytology (FNAC) breast is generally considered a reliable diagnostic tool to distinguish non-proliferative from proliferative breast lesions. Nevertheless, differentiating these breast lesions on FNAC poses a diagnostic challenge. Modified Masood Scoring System (MMSS) based on cytomorphological examination has been used to help in differentiating these lesions.Material and methods: A total of 67 patients were included in this prospective study done from November 2012 to May 2014 and the breast lesions were cytologically categorized by conventional and as per MMSS criteria, followed by comparison to a histopathological examination, which was taken as a gold standard. Relevant frequencies and proportions were calculated along with the sensitivity and specificity of the MMSS.Results: The age of the patients ranged from 15 to 85 years with a mean age of 44.3 ± 14.8 years. Females predominated in the study and right-sided breast lesions were more common compared to the left side. Overall diagnostic specificity (100%) and accuracy (97%) were higher using MMSS as compared to conventional cytology in which case specificity was 83.6% and accuracy was 82.1%.Conclusions: Cytological grading system based on MMSS allowed accurate and reproducible diagnosis compared to the standard histopathological diagnosis. It is essential to differentiate non-proliferative lesions from proliferative lesions as the line of treatment and prognosis varies.

Fibrocystic Changes of the Breast: Radiologic-Pathologic Correlation of MRI.

Breast MRI provides high sensitivity but modest positive predictive value for identifying breast cancers, with approximately 75% of MRI-guided biopsies returning benign pathologies. Fibrocystic change (FCC) is a descriptive term used colloquially by many radiologists (and falling out of favor with many pathologists) to refer to several benign entities encountered in the breast. Many of the benign entities believed to comprise FCC can show enhancement on MRI. Recognizing the pathologic correlates of these enhancing lesions should help guide management after such a result on MRI-guided biopsy. Premenopausal women may present with clinical symptoms attributed to FCC, including pain, nipple discharge, breast lumps, or discrete masses. Benign entities associated with FCC include proliferative lesions such as usual ductal hyperplasia and sclerosing adenosis, and nonproliferative lesions including cysts, apocrine metaplasia, and stromal fibrosis. Fibrocystic change can be diffuse or focal. Diffuse FCC usually presents as non-mass enhancement (NME), often with persistent kinetics. Focal FCC can present as an irregular mass or focus with variable enhancement patterns including washout kinetics. Following a benign concordant MRI-guided biopsy result of one or more of the above entities, follow-up with MRI in 12 months is reasonable. Accurate radiologic-pathologic correlation can be achieved when careful review of histologic findings is carried out in the context of MRI features.

Treatment Outcomes of Proliferative vs. Non-proliferative Adult Lupus Nephritis: A 10-Year Follow-Up.

IntroductionSystemic lupus erythematosus (SLE) is a systemic disease with clinically heterogeneous outcomes. Lupus nephritis (LN) is a common complication of SLE. LN impacts clinical SLE outcomes both directly, in the form of target organ damage, and indirectly, through the adverse effects of immunosuppressive therapy.Patients & methodsThe study included 402 SLE cases with biopsy-proven lupus nephritis who were under follow-up for the past 13 years at Mansoura Urology and Nephrology Center, Egypt. We studied the differences in outcome among various LN classes and between 275 proliferative cases and 102 non-proliferative cases.ResultsClass IV was the main LN class in our series with renal survival of 60% at 10 years. The major induction regimen after the first biopsy was cyclophosphamide. Mycophenolate mofetil was the main induction and adjunctive regimen after the second biopsy. The mean follow-up period was 6.7 + 5.2 years. Higher serum creatinine, proteinuria, activity, and chronicity indices were noted in proliferative LN. Patients suffering from proliferative lesions received higher immunosuppression and demonstrated higher morbidity than those with non-proliferative lesions. Remission was higher among the non-proliferative compared to the proliferative group.ConclusionsSerum creatinine, proteinuria, and LN class were the most relevant prognostic factors for renal survival among Egyptian LN patients.

Mammographic features of benign breast lesions and risk of subsequent breast cancer in women attending breast cancer screening.

To evaluate the mammographic features in women with benign breast disease (BBD) and the risk of subsequent breast cancer according to their mammographic findings. We analyzed data from a Spanish cohort of women screened from 1995 to 2015 and followed up until December 2017 (median follow-up, 5.9 years). We included 10,650 women who had both histologically confirmed BBD and mammographic findings. We evaluated proliferative and nonproliferative BBD subtypes, and their mammographic features: architectural distortion, asymmetries, calcifications, masses, and multiple findings. The adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for breast cancer were estimated using a Cox proportional hazards model. We plotted the adjusted cumulative incidence curves. Calcifications were more frequent in proliferative disease with atypia (43.9%) than without atypia (36.8%) or nonproliferative disease (22.2%; p value < 0.05). Masses were more frequent in nonproliferative lesions (59.1%) than in proliferative lesions without atypia (35.1%) or with atypia (30.0%; p value < 0.05). Multiple findings and architectural distortion were more likely in proliferative disease (16.1% and 4.7%) than in nonproliferative disease (12.8% and 1.9%). Subsequent breast cancer occurred in 268 (2.5%) women. Compared with women who had masses, the highest risk of subsequent breast cancer was found in those with architectural distortions (aHR, 2.21; 95% CI, 1.16-4.22), followed by those with multiple findings (aHR, 1.89; 95% CI, 1.34-2.66), asymmetries (aHR, 1.66; 95% CI, 0.84-3.28), and calcifications (aHR, 1.60; 95% CI, 1.21-2.12). BBD subtypes showed distinct mammographic findings. The risk of subsequent breast cancer was high in those who have shown architectural distortion, multiple findings, asymmetries, and calcifications than in women with masses. • The presence of mammographic findings in women attending breast cancer screening helps clinicians to assess women with benign breast disease (BBD). • Calcifications were frequent in BBDs with atypia, which are the ones with a high breast cancer risk, while masses were common in low-risk BBDs. • The excess risk of subsequent breast cancer in women with BBD was higher in those who showed architectural distortion compared to those with masses.

The impact of mammographic screening on the subsequent breast cancer risk associated with biopsy-proven benign breast disease

Data on the risk of breast cancer following a benign breast disease (BBD) diagnosis were derived predominantly from populations of women biopsied before the widespread use of mammographic screening and in whom these lesions were mostly incidental findings. Whether or not similar risk associations are seen when these lesions are detected in mammographically screened populations is unknown. To address this, we examined the variation in BBD and breast cancer risk associations by the calendar time of BBD diagnosis (pre- vs. post-mammography era [before vs. 1985 and after]) in a nested case–control study within the Nurses’ Health Study (NHS) and NHSII BBD subcohort (488 cases; 1908 controls). We performed logistic regression analysis, adjusting for matching factors and potential confounders, to estimate odds ratio (ORs) and 95% confidence interval (CI) for the association between BBD subtype (non-proliferative, proliferative without atypia, proliferative with atypical hyperplasia (AH)) and subsequent breast cancer risk. When compared with non-proliferative lesions, both proliferative lesions without atypia (PWA) and AHs were associated with similar levels of risk in the pre-mammographic (pre) and post-mammographic (post) time periods (PWA: OR [95% CI] = 1.73 [1.27, 2.36] pre vs. 1.12 [0.73, 1.74] post; AH: 4.41 [2.90, 6.70] pre vs. 3.69 [2.21, 6.15] post). The interaction by mammography era was not statistically significant (p-interaction = 0.47). These results suggest that the risk associations reported for BBD subtypes in the pre-mammography era remain valid for BBD detected after the widespread implementation of mammographic screening.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Rabbit

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and non-proliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the laboratory rabbit used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Non-proliferative and Proliferative Lesions of the Non-human Primate (M. fascicularis).

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP) and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the nonhuman primate used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Dog.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the societies of toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying lesions observed in most tissues and organs from the dog used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions, lesions induced by exposure to test materials, and relevant infectious and parasitic lesions. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

International Harmonization of Nomenclature and Diagnostic Criteria (INHAND): Nonproliferative and Proliferative Lesions of the Minipig.

The INHAND (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions) Project (www.toxpath.org/inhand.asp) is a joint initiative of the Societies of Toxicologic Pathology from Europe (ESTP), Great Britain (BSTP), Japan (JSTP), and North America (STP) to develop an internationally accepted nomenclature for proliferative and nonproliferative lesions in laboratory animals. The purpose of this publication is to provide a standardized nomenclature for classifying microscopic lesions observed in most tissues and organs from the minipig used in nonclinical safety studies. Some of the lesions are illustrated by color photomicrographs. The standardized nomenclature presented in this document is also available electronically on the internet (http://www.goreni.org/). Sources of material included histopathology databases from government, academia, and industrial laboratories throughout the world. Content includes spontaneous lesions as well as lesions induced by exposure to test materials. Relevant infectious and parasitic lesions are included as well. A widely accepted and utilized international harmonization of nomenclature for lesions in laboratory animals will provide a common language among regulatory and scientific research organizations in different countries and increase and enrich international exchanges of information among toxicologists and pathologists.

Conditioning Regimens in Long-Term Pre-Clinical Studies to Support Development of Ex Vivo Gene Therapy: Review of Nonproliferative and Proliferative Changes.

Hematopoietic stem cell gene therapy has become a successful therapeutic strategy for some inherited genetic disorders. Pre-clinical toxicity studies performed to support the human clinical trials using viral-mediated gene transfer and autologous hematopoietic stem and progenitor cell (HSPC) transplantation are complex and the use of mouse models of human diseases makes interpretation of the results challenging. In addition, they rely on the use of conditioning agents that must induce enough myeloablation to allow engraftment of transduced and transplanted HSPC. Busulfan and total body irradiation (TBI) are the most commonly used conditioning regimens in the mouse. Lenticular degeneration and atrophy of reproductive organs are expected histopathological changes. Proliferative and nonproliferative lesions can be observed with different incidence and distribution across strains and mouse models of diseases. The occurrence of these lesions can interfere with the interpretation of pre-clinical toxicity and tumorigenicity studies performed to support the human clinical studies. As such, it is important to be aware of the background incidence of lesions induced by different conditioning regimens. We review the histopathology results from seven long-term studies, five using TBI and two using busulfan.

Proliferative and Nonproliferative Lesions of the Rat and Mouse Central and Peripheral Nervous Systems: New and Revised INHAND Terms.

Harmonization of diagnostic terminology used during the histopathologic analysis of rodent tissue sections from nonclinical toxicity studies will improve the consistency of data sets produced by laboratories located around the world. The INHAND Project (International Harmonization of Nomenclature and Diagnostic Criteria for Lesions in Rats and Mice) is a cooperative enterprise of 4 major societies of toxicologic pathology to develop a globally accepted standard vocabulary for proliferative and nonproliferative lesions in rodents. A prior manuscript (Toxicol Pathol 2012;40[4 Suppl]:87S-157S) defined multiple diagnostic terms for toxicant-induced lesions, common spontaneous and age-related changes, and principal confounding artifacts in the rat and mouse central nervous system (CNS) and peripheral nervous system (PNS). The current article defines 9 new diagnostic terms and updates 2 previous terms for findings in the rodent CNS and PNS, the need for which has become evident in the years since the publication of the initial INHAND nomenclature for findings in rodent neural tissues. The nomenclature presented in this document is also available electronically on the Internet at the goRENI website (http://www.goreni.org/).

P53 Expression in benign Breast Disease Development: A Systematic Review.

Background:Benign breast disease (BBD) is one of main breast cancer risk factors. Dysfunctions on p53 protein, which has a genome protective role, have been related to breast cancer developments. However, its role on BBD development is still unclear. Methods:A systematic review of literature was proceeded according to PRISMA-P guidelines. PubMed, BVS, MEDLINE and Scholar Google were used as databases, complemented by a manual search in articles references. Articles searches were conducted from May to July 2019 and publications in English, Spanish and Portuguese were selected. P53 expression was set as outcome among women with BBD and were included only articles with good quality according STROBE tools. Data concerning p53 expression frequencies were independently extracted by two review authors, and eligible articles were synthesized. Results:From 12 studies selected for this review, the majority analyzed p53 expression in non-proliferative lesions and general p53 expressions ranged from 0 to 100%. P53 expression was more frequently observed in cases series studies (91.7%) and in studies conducted in Occidental Europe (41.7%). P53 expression was more frequent among tissues with fibrocystic disease (22.5%) and fibroadenoma (22.5%).Conclusion:When compared with all breast tissues types, benign breast disease corresponds to 34.39% of p53 expression. Second outcomes were not evaluated because the heterogeneity observed in selected studies. In addition, more studies considering ethnicity and benign breast disease classification should also be considered for further analysis.

Abstract NG15: Investigation of relationships between breast cancer risk factors and bilateral mammographic breast density asymmetry among women undergoing diagnostic image-guided breast biopsies

Introduction: The etiology of breast cancer remains an area of ongoing investigation. Improving our understanding of factors associated with breast cancer development will strengthen the utility of risk prediction strategies and improve risk stratification. Mammographic breast density remains one of the most influential breast cancer risk factors, with 4 to 6 fold elevated risk observed among women with the highest compared to the lowest levels. These associations have consistently been observed irrespective of the method (visual or automated), used to quantify breast density, showing the robustness of the associations. An understudied breast cancer risk factor is the bilateral asymmetry of mammographic features, with prior studies suggesting that women with higher levels of breast asymmetry may be at elevated breast cancer risk. Increasingly, studies are recognizing the potential of bilateral breast asymmetry defined by mammographic breast density in determining breast cancer risk. Recently, Eriksson and colleagues highlighted a strong influence of breast asymmetry within a model they developed to predict short-term breast cancer risk among women attending breast screening. They observed that the contribution to the model of asymmetry in mammographic breast density, microcalcifications, and masses between the breasts was as substantial as the total number of microcalcifications and masses found within a mammogram, indicating that differences between the breasts may be an important risk marker. To help further understand associations between breast cancer risk factors and asymmetry of breast density, particularly among women at elevated risk for breast cancer, we evaluated risk factor relationships with the bilateral asymmetry of volumetric measures of global and local breast density across the spectrum of premalignant and invasive breast cancer diagnoses. Methods: This study included 882 women enrolled as part of the National Cancer Institute9s Breast Radiology Evaluation and Study of Tissues (BREAST)-Stamp Project (2007-2010). The BREAST-Stamp Project is a cross-sectional molecular epidemiologic study that aims to understand how novel breast density measures are related to breast cancer etiology. Women were enrolled if they were referred for diagnostic image-guided breast biopsy following an abnormal mammogram at the University of Vermont Medical Center, and had not previously been diagnosed or treated for cancer, undergone breast surgery within one year or received chemoprevention. Risk factor data were collected at study enrolment via interview and self-administered questionnaires. Breast density measures were estimated using Single X-ray Absorptiometry (SXA), a technique in which an SXA breast density phantom was affixed to the compression paddle of the mammography machine during routine mammography so that it was included in the X-ray field. It served as a reference standard to estimate volumetric breast density. Breast density was assessed using pre-biopsy craniocaudal full-field digital mammograms of both the ipsilateral (affected) and contralateral (unaffected) breast. Firstly, global density from each laterality was determined as percent fibroglandular volume (%FGV). Secondly, localized volumetric density measures were estimated following identification of the biopsy site on the ipsilateral pre-biopsy mammogram by the study radiologist and identifying the corresponding site on the contralateral mammogram. The SXA estimated %FGV in a perilesional volume twice the size of, but excluding, the biopsy target, centered at the biopsy site. Previous estimates of reproducibility for the SXA test phantoms demonstrated a repeatability SD of 2%, with a ±2% accuracy for the entire thickness and density ranges. Breast density asymmetry was defined as an absolute bilateral difference in measures when subtracting the breast density measures of the contralateral breast from the ipsilateral measures. Spearman9s correlations (rho) examined associations between breast density measures of the left and right breasts. To determine relationships between breast cancer risk factors (defined as categorical variables) and measures of bilateral breast density asymmetry, analysis of covariance (ANCOVA) models (PROC GLM) were used. Analyses were conducted at the per woman level using SAS. Probability values of Citation Format: Maeve Mullooly, Shaoqi Fan, Ruth M. Pfeiffer, Brian Sprague, Pamela M. Vacek, Donald L. Weaver, John A. Shepherd, Amir Pasha Mahmoudzadeh, Jeff Wang, Serghei Malkov, Jason M. Johnson, Sally D. Herschorn, Gretchen L. Gierach. Investigation of relationships between breast cancer risk factors and bilateral mammographic breast density asymmetry among women undergoing diagnostic image-guided breast biopsies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG15.

Abstract PD3-05: The impact of mammographic screening on the subsequent breast cancer risk associated with biopsy-proven benign breast disease

Abstract Background: Benign breast disease (BBD) is a term that encompasses a heterogeneous group of lesions with different levels of subsequent breast cancer risk. Large, epidemiologic follow-up studies have consistently shown that proliferative lesions without atypia are associated with a 1.5-2-fold increase in risk whereas atypical hyperplasias are associated with a 4-5-fold increase in risk. However, these data were derived primarily from populations of women who, for the most part, were biopsied before the widespread use of screening mammography and in whom these lesions were incidental findings. Whether or not similar levels of subsequent breast cancer risk are found when these lesions are detected in mammographically screened populations has not been previously investigated. Methods: To address this issue, we performed a nested case-control study within the Nurses’ Health Study (NHS) and NHSII BBD cohorts, including 488 women who had biopsy-proven BBD and on average 9 years later developed breast cancer (cases) and 1,908 women who had biopsy-proven BBD and did not develop breast cancer (controls). We performed logistic regression, adjusting for matching factors and potential confounders, to estimate odds ratios (OR) and 95% confidence intervals (CI) for developing subsequent breast cancer by BBD subtype. We stratified the analyses by the calendar time of BBD diagnosis (pre- vs. post-mammographic era [before vs. after 1985]) and the method of BBD detection (mammogram vs. self-exam/physician’s exam). Interaction tests were performed using the Wald test for product terms. Results: During the pre-mammographic era, proliferative lesions without atypia were associated with a 1.78-fold higher risk of breast cancer (95% CI=1.31-2.42) and atypical hyperplasia was associated with a 4.61-fold higher risk (95% CI=3.05-6.97) compared with nonproliferative lesions. The risk association was similar but slightly weaker during the post-mammographic era (proliferative lesions without atypia vs. nonproliferative: OR=1.14, 95% CI=0.74-1.76; atypical hyperplasia vs. nonproliferative: OR=3.54, 95% CI=2.14-5.88). When the analysis was stratified by the method of BBD detection, the risk association was similar but slightly attenuated in the stratum of BBDs found on self-exam or physician’s exam (atypical hyperplasia vs. nonproliferative: OR=4.16, 95% CI=2.81-6.16; proliferative without atypia vs nonproliferative: OR=1.54, 95% CI= 1.15-2.07) than in the stratum of BBDs found on mammography (atypical hyperplasia vs. nonproliferative: OR=5.54, 95% CI=2.57-12.0; proliferative without atypia vs nonproliferative: OR=1.15, 95% CI=0.80-3.31). The interaction by calendar time of BBD diagnosis and the method of BBD detection was not statistically significant (p-interaction=0.51 when stratified by pre- (before 1985) vs. post-mammography era (since 1985) and p-interaction=0.09 when stratified by the method of benign breast disease detection). Conclusions: Our data suggest that the risk associated with BBD subtypes initially reported from women biopsied in the pre-mammographic era remain valid for BBD detected after the widespread use of screening mammography was established. Citation Format: Francisco Beca, Hannah Oh, Laura C Collins, Rulla M Tamimi, Stuart J Schnitt. The impact of mammographic screening on the subsequent breast cancer risk associated with biopsy-proven benign breast disease [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD3-05.

Contribution of Clinically Indicated Repeat Renal Biopsy in Indian Patients with Lupus Nephritis.

Background:Repeat renal biopsy is usually done for lupus nephritis (LN) flare or resistant disease. We analyzed the changes between first and repeat biopsy and the contribution of repeat biopsy on renal outcome in LN patients.Methods:This was a retrospective study carried out at a tertiary care center in India. Sixty-two LN patients who underwent repeat biopsy for clinical indications, between January 2012 to December 2016, were included. Clinical and histological parameters at first and second biopsies were compared. Logistic regression analysis was done to determine parameters on repeat biopsy predicting response at last visit.Results:Repeat biopsy was done for relapse in 56% and for resistant disease in 44% patients. Seven (13.7%) out of 51 patients with baseline proliferative histology converted to non-proliferative lesion on second biopsy, while 2 (18.2%) out of 11 with baseline non-proliferative lesion converted to proliferative lesion on second biopsy. On repeat biopsy, the presence of endocapillary proliferation decreased, whereas glomerulosclerosis, interstitial fibrosis/tubular atrophy (IFTA), and glomerular basement membrane thickening increased. At the last visit (median follow-up of 38.6 months after first biopsy and 13.8 months after second biopsy), 79% of patients were in remission and 6.5% needed renal replacement therapy. The presence of IFTA >30% and thrombotic microangiopathy (TMA) on second biopsy independently predicted response at last visit.Conclusion:In Indian patients with LN, chronicity markers and superimposed membranous pattern increased on repeat biopsy done for clinical indications. The presence of IFTA and TMA on second biopsy predicted response at last visit.