Immunohistochemical findings and clinicopathological features of breast cancers with pathogenic germline mutations in Non-BRCA genes.

Deleterious germline mutations in multiple genes confer an increased breast cancer (BC) risk. Immunohistochemical (IHC) expression of protein products of mutated high-risk genes has not been investigated in BC. We hypothesized that pathogenic mutations may lead to an abnormal IHC expression pattern in the tumor cells. BCs with deleterious germline mutations in CHEK2, ATM, PALB2 & PTEN were identified. Immunohistochemistry was performed using Dako staining platform on formalin fixed paraffin embedded tumor tissue. Primary antibodies for PALB2 (ab202970), ATM [2C1(1A10)}, CHK2 (EPR4325), and PTEN (138G6) proteins were used for BCs with respective deleterious mutations. IHC expression was assessed in tumor and adjacent benign breast tissue. Total 27 BCs with 10 CHEK2, 9 ATM, 6 PALB2 & 2 PTEN deleterious germline mutations were identified. IHC staining was performed on 8 CHEK2, 7 ATM, 6 PALB2 & 2 PTEN cases. Abnormal CHEK2 IHC staining was identified in 7/8(88%) BCs. Three distinct CHK2 IHC patterns were noted: 1) Strong diffuse nuclear positivity (5 BC), 2) Null-pattern (2 BC), & 3) Normal breast-like staining in 1 BC Four of 5 (80%) strong CHK2 staining BC had missense CHEK2 mutations. Null-pattern was present with a missense & a frameshift mutation. Normal breast-like CHEK2 IHC staining pattern was present in 1 BC with CHEK2 frameshift mutation. Loss of nuclear/cytoplasmic PTEN IHC expression was noted in 2 in-situ carcinomas. Abnormal PTEN and CHK2 IHC were present in atypical ductal hyperplasia and flat epithelial atypia. ATM and PALB2 IHC expression patterns were similar in tumor cells and benign breast epithelium: mild to moderate intensity nuclear and cytoplasmic staining. We report abnormal CHEK2 IHC expression in 88% of BCs with pathogenic CHEK2 mutations. With PTEN and CHEK2 pathogenic mutations, abnormal IHC patterns are seen in early atypical proliferative lesions. IHC may be applied to identify CHEK2 & PTEN mutated BCs and precursor lesions.

Optical coherence tomography biomarkers DROL, PROS, SND, hyperreflective walls of foveal cystoid spaces as predictors of central macular thickness and visual acuity in diabetic macular edema treated with intravitreal ranibizumab.

PURPOSE: This study aims to establish DROL (disruption of retinal outer layers), PROS (photoreceptor outer segment length), SND (subfoveal neuroretinal detachment), and hyperreflective walls of foveal cystoid spaces (HRW) as optical coherence tomography (OCT) biomarkers and predictors of central macular thickness (CMT) and visual acuity in diabetic macular edema (DME) treated with intravitreal ranibizumab (IVR). METHODS: In this prospective, interventional study performed at a tertiary care center over a span of 1 year from December 2021 to December 2022, 50 eyes of 46 patients of DME were included. Visual acuity and spectral domain OCT imaging were performed at baseline. Using inbuilt calipers on SD-OCT, the horizontal extent of DROL and the vertical extent of PROS were measured manually. SND and HRW were assessed qualitatively. IVR was administered and patients were followed up at 4, 8, and 12 weeks. RESULTS: The eyes without DROL had statistically significant (P < 0.05) lesser CMT and better BCVA (best-corrected visual acuity) (P < 0.05) after pro re nata injection of IVR. There was a positive correlation between the extent of baseline DROL with final CMT (P < 0.05) and final logMAR BCVA (P > 0.05), whereas negative correlation with the extent of baseline PROS with final CMT (P < 0.05) and final logMAR BCVA (P > 0.05). The presence of HRW and SND predicted non-resolution of CMT and worse visual acuity after treatment with IVR in DME. CONCLUSION: DROL, PROS, SND, and hyperreflective walls of foveal cystoid spaces may be utilized as qualitative as well as quantitative biomarkers to predict the post-treatment CMT and visual acuity in DME.

Human epidermal growth factor receptor-2 (HER2) expression in FIGO3 high-grade endometrial endometrioid carcinoma: Clinicopathologic characteristics and future directions.

OBJECTIVES: To study the expression of HER2 in high-grade FIGO3 endometrial endometroid carcinoma (EEC) and to correlate our findings with the clinicopathologic characteristics of this tumor. METHODS: HER2 expression by immunohistochemistry (IHC) was performed on 10% formalin-fixed paraffin embedded tissue on cases diagnosed as FIGO3 EEC. HER2 expression was interpreted as negative (0), low (1+ and 2+) or positive (3+) using similar criteria as in the breast. HER2 amplification by Fluorescence in situ hybridization (FISH) was performed on cases interpreted as 2+ and 3+ by IHC. RESULTS: One hundred and forty-three FIGO3 EEC were identified. Of these, 70 (49%) cases were HER2 negative (IHC 0), and 73 (51%) cases expressed/amplified HER2 by IHC and/or FISH. Of the 73 cases expressing or amplifying HER2, 59 cases were IHC 1+, 12 cases were IHC 2+, and 2 cases were IHC 3+. FISH testing was performed in 12 cases. Only one of the two HER2 IHC 3+ cases showed HER2 gene amplification by FISH and the other 11 cases were not amplified. The 5-year overall survival (OS) rate for HER2 IHC 1+ cases was 92.20% (95% CI: 83.97-100.00), and the 5-year OS rate for HER2 IHC 2+/3+ cases was 89.50% (95% CI: 56.41-100.00). CONCLUSION: Our findings indicate that about one half of FIGO3 EEC variably expresses HER2 and with the emerging concept of "HER2 low", anti-HER2 agents may be explored as potential therapeutic options in these patients, for possible survival benefits.

Ever Expanding Morphologic Patterns of Mesonephric-like Adenocarcinomas of the Uterine Corpus: A Report of Two Tumors and a Brief Review of the Literature.

Mesonephric-like adenocarcinoma (MLA) of the endometrium shows a variety of morphologic appearances, including small glands, tubules with eosinophilic materials in the lumen, prominent papillary patterns, spindled cells, solid formations, and corded and hyalinized patterns. Unique morphology, characteristic immunohistochemical staining patterns, molecular alterations, and awareness of the pathologists make it possible to identify this tumor accurately. This report of two additional morphologic patterns, intestinal goblet cells mimicking intestinal-type mucinous carcinoma and squamous differentiation with spindle and epithelioid cells mimicking carcinosarcoma of the endometrium will expand the literature on MLA.

Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

Quantitative measurement of retinal nerve fiber layer thickness and its correlation with optical coherence tomography angiography vascular biomarker changes in preclinical diabetic retinopathy.

PURPOSE: The present study was done to assess the use of optical coherence tomography angiography (OCTA) in detecting earlier stages of diabetic retinopathy and for the early management and effective blood glucose control in preclinical diabetic patients for preventing retinal nerve fiber layer (RNFL) thinning. METHODS: A tertiary care center-based prospective observational study was conducted from the year 2021 to 2022 in the Department of Ophthalmology. The study included 50 cases and 50 controls. The parameters analyzed by using OCTA (Topcon 3D OCT-1 Maestro2) were RNFL thickness and peripapillary vessel density. RESULTS: We found that the RNFL thickness in the temporal and superior disc in patients with preclinical diabetic retinopathy was significantly (0.041 and 0.044, respectively) decreased. The duration of diabetes and glycated hemoglobin (HbA1c) were the risk factors for peripapillary vessel density reduction in patients with preclinical diabetic retinopathy (P < 0.001). CONCLUSION: RNFL thinning is an early sign of retinal neurodegeneration and is associated with peripapillary vessel density reduction. Early management and effective blood glucose control in diabetes patients may be beneficial for preventing RNFL thinning in superior and temporal disc.

Breast Carcinoma With Tubulopapillary Features Has a Distinct Immunophenotypic and Molecular Signature: A Report of Two Tumors and Literature Review.

Breast carcinoma with tubulopapillary features is a newly described entity associated with poor prognosis with only 14 tumors reported in the literature. We report 2 additional tumors and identify novel immunohistochemical and molecular features of the tumor. The first tumor was from a 72-year-old woman with nonmetastatic breast carcinoma and the second was from a 32-year-old woman with metastatic breast carcinoma who received neoadjuvant therapy. Both tumors had high-grade nuclear features with a distinctive morphology characterized by infiltrating open glands with intratubular papillary and micropapillary projections in >90% of the invasive carcinoma. In addition to the usual predictors of aggressive behavior, both tumors showed a high expression of p16 and SOX10, which has not been previously described. Targeted tumor sequencing revealed pathogenic variants of TP53 in both tumors, in agreement with previous reports. Prior studies have shown a correlation between p16 and SOX10 expression with high-grade features and worse prognosis; typically seen in triple-negative carcinomas as demonstrated in both of our tumors. However, not all reported tumors of breast carcinoma with tubulopapillary features have demonstrated a triple-negative profile as there are a few reports of tumors with estrogen receptor and/or human epidermal growth factor 2 expression. Due to their distinct morphologic and molecular characteristics, breast carcinoma with tubulopapillary features may represent a new breast cancer histologic subtype.

Pathological response in mucinous carcinoma of breast after neoadjuvant therapy - a multi-institutional study.

Although mucinous carcinoma (MC) is considered a favorable histologic subtype of invasive breast cancer (BC), a subset of MC is managed with neoadjuvant therapy (NAT). The clinical and pathologic features of MC following NAT are not well characterized. The aim of this study is to characterize pathologic response in patients with MC treated with NAT, including neoadjuvant endocrine therapy (NET), neoadjuvant chemotherapy (NCT), and Herceptin-targeted NCT (H-NCT). We conducted a retrospective cohort study of 28 patients with MC who received preoperative adjuvant therapy followed by resection from three institutions between 2010 and 2020. Demographic and clinical information were retrieved from the medical records. Pathologic review of the post NAT resection specimens was performed including tumor grading, tumor size, staging, residual tumor cellularity, estrogen receptor (ER) and HER2 status. Nine (32 %) patients with ER+/HER2- MC received NET, 8 (29 %) ER+/HER2- MC were treated with NCT only and 11 (39 %) HER2+ MC received HER2-targeted NCT (H-NCT). The HER2+ MC patients were younger (45 vs. 64 years; p = 0.006). The HER2+ MC were of higher grade (p = 0.03) and more likely to be multifocal (p = 0.008). Only 2 of 28 (7 %) MC (both HER2+) showed complete pathologic response with residual acellular mucin pools. Persistent mass-forming mucin pools were present in 26 (93 %) cases. The residual tumor cellularity was markedly reduced (≤5 %) in H-NCT treated MC (11/11, 100 %), followed by NET group (6/9, 67 %) and NCT only group (4/8, 50 %) (p = 0.011). Similarly, a higher rate of pathologic response (pCR/RCB-I) was observed in H-NCT (7/11, 64 %), followed by NET group (5/9, 56 %), and NCT only group (1/7, 13 %) (p = 0.053). Post-therapy, all HER2+ MC were smaller than 2 cm and ypT size was significantly smaller in H-NCT group (11/11, 100 %) versus combined NET (5/9, 55 %) and NCT only groups (4/8, 50 %) (p = 0.029). We conclude that ER-/HER2+ and ER+/HER2-mucinous carcinomas of the breast show robust pathological response to neoadjuvant HER2 targeted and endocrine therapy, respectively. Our findings suggest that MC may show good response to endocrine therapy.

Low-level expression of human Epidermal growth Factor Receptor-2 (HER2) in High-Grade Mullerian Tumors: Implications for therapy decision making.

Introduction: Reclassification of HER2-negative breast cancers to HER2 low-level expression allowed targeted anti-HER2 therapy in about 60% of patients, improving outcome. The high recurrence rates and often dismal outcomes with current therapies of high-grade Mullerian carcinomas, offers opportunity to explore anti-HER2 therapies in the gynecologic tract carcinomas. We investigated HER2 low expression as currently defined in breast carcinomas. Methods: We reviewed all high-grade Mullerian cancers between 2016 and 2021, where HER2 by IHC and/or FISH tests were available. Additional clinical information was recorded, and statistical analysis was performed using SPSS (version 27). Results: Forty (49.4%) tumors were endometrial, 20 (24.7%) ovarian, 16 (19.8%) fallopian tubal, and 5 (6.2%) primarily peritoneal. Overall, 17 (21.0%) were HER2 positive (IHC 3+/IHC 2+/FISH amplified), 31 (38.3%) HER2 low (IHC 1+/2+/FISH non-amplified), and 30 (37.0%) were HER2 negative (IHC = 0). HER2 low expression was noted in 15% ovarian, 25% fallopian tubal, 53% endometrial, and 60% peritoneal tumors; 34% and 21% of serous carcinomas, 63% and 13% of carcinosarcomas, and 67% and 33% of endometrioid carcinomas were HER2 low and HER2 positive respectively. HER2 negative and HER2 low expression had a significant association with primary tumor location (p = 0.001); endometrium and peritoneal tumors were more likely to be HER2 low and HER2 negative. During a mean follow-up of 13.2 months (range: 1-34), 5% of the patients were deceased. Conclusions: Based on the current HER2-low recommendations in the breast, about one-third of patients with high-grade Mullerian carcinomas might qualify for anti-HER2 therapy with a potential for improved progression-free and overall survival.

Outcomes of Geriatric Hip Fractures in a Tertiary Referral Center in Malaysia During the COVID-19 Pandemic.

Introduction With the advancing age of the population, there are an increasing number of patients with geriatric hip fractures. Despite the advancement of surgical knowledge and improvement of implant designs to treat geriatric hip fractures, mortality and morbidity remain high among these frail patients. In conjunction with the COVID-19 pandemic, the collateral damage dealt to these patients remains unknown as scarce resources are funneled to deal with the pandemic. This study is geared to investigate the surgical outcomes of patients with geriatric hip fractures who were admitted during the initial phase of the COVID-19 pandemic. Methods This retrospective study was carried out at Hospital Kuala Lumpur, the largest public hospital in the capital of Malaysia, from March 1, 2020, to March 1, 2021. All patients of age 60 years and above were screened for suitability. Only patients who had undergone surgical intervention during the study period were included in this study. Patients' demographic data, mechanism of injury, waiting time for surgery, type of surgery, complications and ambulatory status were obtained from the medical records. Univariate analysis was performed to determine the factors associated with complications as well as the post-operative ambulatory status of the patients. Results A total of 52 patients were included in this study, with a median age of 72 years. The majority of the patients were Chinese (n=21, 40.4%). This was followed by Malay and Indian (n=14, 26.9% each) and other ethnicity (n=3, 5.8%). More than three-quarters of the patients had a trivial injury such as a fall due to a miss-step (n=16, 30.8%) and slip (n=16, 30.8%) and a fall due to dizziness (n=8, 15.4%). Only 12 patients (23.1%) sustained hip fractures due to trauma. The median time to surgery for these patients was 5 days (interquartile range: 4 days). Most of these patients underwent total hip replacement (n=30, 57.7%). This was followed by unipolar hemiarthroplasty (n=11, 21.2%), bipolar hemiarthroplasty (n=10, 19.2%) and internal fixation (n=1, 1.9%). Among these patients, six of them had documented complications. There were periprosthetic joint infection (n=2, 3.8%), dislocation (n=2, 3.8%), hematoma formation (n=1, 1.9%) and seroma (n=1, 1.9%). Six months after the surgery, most of the patients were able to ambulate, albeit some patients required walking aid such as walking stick and walking frame. Univariate analysis showed that all the factors were not associated with the complications and the post-operative ambulatory status of the patients. Conclusion  The incidence of geriatric hip fractures remains high during the COVID-19 pandemic despite the movement control order (MCO) being enforced in Malaysia. With prompt surgical intervention, most of the patients can regain ambulatory status, albeit with a walking aid.

Recurrent Primary Paget Disease of Vulva with Paget-Like Epithelial Cells in Papillary Dermis: Displaced or Invasion?

While histological diagnosis of Paget disease of vulva is mostly straightforward, identifying and confirming invasion can be challenging. Often invasion is accompanied by epidermal hyperplasia, marked inflammatory response and desmoplastic reaction. Diagnosis of invasion in Paget disease portends a poor outcome. We report findings from a recurrent primary vulvar Paget disease where overall histomorphology of possible invasive disease is unusual and raises a possibility of displacement of Paget cells in the dermis. We compare histology of the index case with known invasive vulvar Paget disease cases retrieved from our pathology archives. Unique histomorphology in the index case suggests a possibility of previous excision related dermal displacement of Paget cells.

Impact of learning effect on reliability factors and global indices in visual field testing by standard automated perimetry in normal healthy subjects and primary open-angle glaucoma patients to obtain an accurate baseline perimetry chart.

Purpose: To record and evaluate the reliability parameters (fixation loss (FL) %, false positive (FP) %) and global indices (mean sensitivity (MS), mean deviation (MD), pattern standard deviation in dB) in three visual field test sessions within two weeks to assess the learning effect in normal healthy subjects and POAG patients and comparison of learning effect gender wise and age wise in primary open-angle glaucoma (POAG) patients. Methods: This study was a prospective observational study. An oculus visual field testing was done and analyzed in 30 eyes of POAG patients and 30 eyes of normal healthy subjects in three visits. Results: There were 16 (53.3%) males and 14 (46.6%) females in the POAG group and 16 (53.33%) males and 14 (46.66%) females in the normal healthy subject group. A significant difference in data change between each visit in FL, FP, MD, MS was found though the difference was more pronounced in the second visit than in the third visit. The pattern standard deviation does not change significantly in subsequent visits in both groups. Gender wise and age wise no significant difference was found in the POAG group. Conclusion: Significant improvement in reliability parameters and global indices with each subsequent visit in both the POAG group and normal patients signifies the importance of learning effect on these parameters and the need to perform at least three tests to get the baseline perimetry chart, especially in POAG patients, while in normal subjects, second perimetric result can be accepted. It was also concluded that the learning effect is not influenced by age and gender.

Mammary stromal-epithelial lesions with myofibroblastic stroma and HMGA2 overexpression linked smooth muscle differentiation, a case series from single institution.

Fibroadenoma and phyllodes tumor are the prototypical mammary fibroepithelial lesions (FELs). Recently, a subset of FELs, identified as stromal-epithelial lesion (SEL) with myofibroblastic stroma have been labelled as myofibroepithelial nodule (MFN). The MFN stromal cells are diffusely positive for SMA immunostaining and frequently show unusual histological features including irregular borders. There is limited literature on FELs with myofibroblastic or smooth muscle stroma. The etiology of the variation in the FEL stromal histology and its clinical significance is unknown. In this short report we describe clinicopathologic features of six FELs with myofibroblastic and/or smooth muscle stroma. We also report immunohistochemical overexpression of HMGA2 in 2 FELs that contained stromal smooth muscle differentiation suggesting a link to mammary myoid hamartoma. On limited follow up all the 6 FELs with myofibroblastic or smooth muscle stroma had benign outcome. The HMGA2 overexpressing FEL with smooth muscle stroma and myoid hamartoma of the breast show overlapping etiology, and histological features.

Whole slide image features predict pathologic complete response and poor clinical outcomes in triple-negative breast cancer.

INTRODUCTION: Breast cancers are complex ecosystem like networks of malignant cells and their associated microenvironment. Applications for machine intelligence and the tumoral microenvironment are expanding frontiers in pathology. Previously, computational approaches have been developed to quantify and spatially analyze immune cells, proportionate stroma, and detect tumor budding. Little work has been done to analyze different types of tumor-associated stromata both quantitatively and computationally in relation to clinical endpoints. METHODS: We aimed to quantify stromal features from whole slide images (WSI) including stromata (myxoid, collagenous, immune) and tumoral components and combined them with traditional clinical and pathologic parameters in 120 triple-negative breast cancer (TNBC) patients treated with neoadjuvant chemotherapy (NAC) to predict pathologic complete response (pCR) and poor clinical outcomes. RESULTS: High collagenous stroma on WSI was best associated with lower rates of pCR, while combined high proportionated stroma (myxoid, collagenous, and immune) most optimally predicted worse clinical survival outcomes. When combining clinical, pathologic, and WSI features, Receiver Operator Characteristics (ROC) curves for LASSO features was up to 0.67 for pCR and 0.77 for poor outcomes. CONCLUSION: The techniques demonstrated in the present study can be performed with appropriate quality assurance. Future trials are needed to demonstrate whether coupling applications for machine intelligence, inclusive of the tumor mesenchyme, can improve outcomes prediction for patients with breast cancer.

Diagnostic utility of PRAME immunohistochemistry in PEComa family of tumors and morphologic mimics with emphasis on the gynecologic tract.

Perivascular epithelioid cell tumors (PEComas), rare mesenchymal tumors with myomelanocytic differentiation, can be a diagnostic challenge, often requiring a panel of immunohistochemical markers. Preferentially expressed antigen in melanoma (PRAME) is a relatively new antigen with utility in diagnosing melanomas. This study aimed to survey PRAME expression patterns in the PEComa family of tumors and morphologic mimics. Twenty cases of PEComas and 27 non-PEComas (10 leiomyosarcomas, 3 smooth muscle tumors of uncertain malignant potential [STUMPs], 11 leiomyomas, 1 uterine inflammatory myofibroblastic tumor [IMT], and 2 low-grade endometrial stromal sarcomas [LGESSs]) were stained with PRAME and compared to previously performed HMB45 and Melan-A stains, when available. Tumors showing no or barely perceptible PRAME staining at 10× were considered negative. Tumors were considered positive if there was full nuclear staining evident at 10× in at least one 10× field. Diffuse staining was defined as positivity in at least 80% of tumor nuclei. Overall, PRAME was expressed in 70% of PEComas, with diffuse positivity in 60%. However, PRAME was not specific for PEComas, with immunopositivity in the majority (70%) of uterine leiomyosarcoma cases, though negative in STUMP, leiomyoma, IMT, and LGESS cases. PRAME sensitivity was 70% and specificity was 74%, while HMB45 was more sensitive (90%) and specific (100%), but only 15% of PEComas showed diffuse staining. Melan-A staining was less common than HMB45 or PRAME, with only 18.8% sensitivity but 100% specificity. Among gynecologic PEComas, PRAME was expressed in 75% overall and enriched among malignant cases (85.7% positive). As part of an immunohistochemical panel, PRAME could be useful in the workup of PEComa cases. In the future, PRAME-specific immunotherapies may be beneficial in treating patients with malignant PEComas.

Prevalence of dry eye, its categorization (Dry Eye Workshop II), and pathological correlation: A tertiary care study.

Purpose: To study the prevalence of dry eye disease (DED), further categorize using DEWS II protocol, grade squamous metaplasia in each group, and determine associated risk factors in a tertiary care hospital. Methods: This cross-sectional hospital-based study screened 897 patients ≥30 years via systematic random sampling. Patients with both symptoms and signs as defined by the Dry Eye Workshop II protocol were considered as DED, further categorized, and subjected to impression cytology. Categorical data were assessed using the Chi-square test. P value < 0.05 was considered statistically significant. Results: In total, 265 (of 897) patients were defined as DED based on the presence of symptoms (DEQ-5 ≥6) and at least one positive sign (fluorescein breakup time [FBUT] <10 s or OSS ≥4). DED prevalence was thus 29.5% with aqueous deficient dry eye (ADDE), evaporative dry eye (EDE), and mixed type seen in 92 (34.71%), 105 (39.62%), and 68 (25.7%) patients, respectively. The risk of developing dry eye was higher in the age above 60 years (33.74%) and in the third decade. Females, urban dwellers, diabetics, smokers, history of previous cataract surgery, and usage of visual display terminal devices were found to be significantly associated with risk factors of DED. Squamous metaplasia and goblet cell loss were more severe in mixed compared to EDE and ADDE. Conclusion: Hospital-based prevalence of DED is 29.5% with a preponderance of EDE (EDE 39.62%, ADDE 34.71%, and mixed 25.71%). A higher grade of squamous metaplasia was seen in the mixed type compared to other sub-types.

Multi-institutional Assessment of Pathologist Scoring HER2 Immunohistochemistry.

The HercepTest was approved 20+ years ago as the companion diagnostic test for trastuzumab in human epidermal growth factor 2 (HER2) or ERBB2 gene-amplified/overexpressing breast cancers. Subsequent HER2 immunohistochemistry (IHC) assays followed, including the now most common Ventana 4B5 assay. Although this IHC assay has become the clinical standard, its reliability, reproducibility, and accuracy have largely been approved and accepted on the basis of concordance among small numbers of pathologists without validation in a real-world setting. In this study, we evaluated the concordance and interrater reliability of scoring HER2 IHC in 170 breast cancer biopsies by 18 breast cancer-specialized pathologists from 15 institutions. We used the Observers Needed to Evaluate Subjective Tests method to determine the plateau of concordance and the minimum number of pathologists needed to estimate interrater agreement values for large numbers of raters, as seen in the real-world setting. We report substantial discordance within the intermediate categories (<1% agreement for 1+ and 3.6% agreement for 2+) in the 4-category HER2 IHC scoring system. The discordance within the IHC 0 cases is also substantial with an overall percent agreement (OPA) of only 25% and poor interrater reliability metrics (0.49 Fleiss' kappa, 0.55 intraclass correlation coefficient). This discordance can be partially reduced by using a 3-category system (28.8% vs 46.5% OPA for 4-category and 3-category scoring systems, respectively). Observers Needed to Evaluate Subjective Tests plots suggest that the OPA for the task of determining a HER2 IHC score 0 from not 0 plateaus statistically around 59.4% at 10 raters. Conversely, at the task of scoring HER2 IHC as 3+ or not 3+ pathologists' concordance was much higher with an OPA that plateaus at 87.1% with 6 raters. This suggests that legacy HER2 IHC remains valuable for finding the patients in whom the ERBB2 gene is amplified but unacceptably discordant in assigning HER2-low or HER2-negative status for the emerging HER2-low therapies.

Inflammatory Myofibroblastic Tumor of the Placenta With Subsequent Successful Pregnancy and Benign Hysterectomy: A Case Report With 59-Month Follow-up.

Inflammatory myofibroblastic tumors (IMT) are rare neoplasms of intermediate malignant potential which have been described in the gynecologic tract, predominantly in the myometrial wall, but also in association with the placenta. Like those in other organs, IMT of the placenta are characterized by molecular abnormalities, most commonly anaplastic lymphoma kinase gene rearrangements, and are often positive for anaplastic lymphoma kinase immunohistochemically. Although the clinical behavior of placental IMTs has so far proven benign, a successful intrauterine pregnancy with subsequent negative hysterectomy following a placental IMT has not been documented. Herein is presented a case of a 27-yr-old noted to have a 2 cm IMT of the extraplacental membranes at delivery, after which the patient received no further treatment. After 56 mo, the patient experienced a subsequent normal delivery in a pregnancy complicated by gestational diabetes. No longer desiring fertility, the patient elected to have a hysterectomy to confirm the absence of IMT at 59 mo and the uterus was unremarkable. This case provides insight into possible outcomes for patients with a rare tumor who may desire future fertility and may otherwise be advised to undergo hysterectomy in the setting of an unclear clinical course.

AMACR Expression is a Potential Diagnostic Marker in Apocrine Lesions of Breast, and is Associated with High Histologic Grade and Lymph Node Metastases in Some Invasive Apocrine Breast Cancers.

BACKGROUND: Carcinoma with apocrine differentiation (AC) is a subtype of breast carcinoma with apocrine features in >90% of the tumor. Molecular studies demonstrate AC has high expression of androgen receptor (AR) mRNA. Pure AC lack estrogen receptor (ER), progesterone receptor (PR), and express AR, with variable human epidermal growth factor 2 (HER2) status. Currently, in triple negative AC, no targetable therapies or specific diagnostic markers exist. MATERIALS AND METHODS: α-Methylacyl CoA racemase (AMACR) expression was investigated as a marker of apocrine differentiation using a single-plex immunoperoxidase stain, and a novel AMACR/p63 dual stain in a subset of cases, across 1) benign apocrine lesions (apocrine metaplasia, adenosis) 2) apocrine DCIS (ADCIS), 3) AC/ invasive ductal carcinoma (IDC) with apocrine features, 4) non-apocrine triple negative breast cancer (TNBC) and 5) IDC, no special type. A sub-set of cases were evaluated by tissue microarray. RESULTS: AMACR expression was increased in both AC and ADCIS, with minimal expression in benign breast tissue, TNBC and IDC, NST cases. In invasive cases, those with positive AMACR (>5% positivity) were significantly associated with higher histologic grade (P = .006), initial N stage (chi squared 0.044), and lack of ER or PR expression (both P < .001), with no correlation with overall survival. Analysis of TCGA breast cancer datasets revealed AMACR expression was significantly higher in molecularly defined apocrine carcinomas relative to basal and luminal subtypes. Moreover, high AMACR expression predicted worse relapse-free and distant-metastasis free survival, among both ER-/PR-/Her2- and ER-/PR-/Her2+ breast cancer cohorts (log-rank P = .081 and .00011, respectively). CONCLUSION: AMACR represents a promising diagnostic and prognostic marker in apocrine breast lesions. Further study is needed to determine the biologic and clinical significance of this protein in AC.

UBE2T promotes breast cancer tumor growth by suppressing DNA replication stress.

Breast cancer is a leading cause of cancer-related deaths among women, and current therapies benefit only a subset of these patients. Here, we show that ubiquitin-conjugating enzyme E2T (UBE2T) is overexpressed in patient-derived breast cancer samples, and UBE2T overexpression predicts poor prognosis. We demonstrate that the transcription factor AP-2 alpha (TFAP2A) is necessary for the overexpression of UBE2T in breast cancer cells, and UBE2T inhibition suppresses breast cancer tumor growth in cell culture and in mice. RNA sequencing analysis identified interferon alpha-inducible protein 6 (IFI6) as a key downstream mediator of UBE2T function in breast cancer cells. Consistently, UBE2T inhibition downregulated IFI6 expression, promoting DNA replication stress, cell cycle arrest, and apoptosis and suppressing breast cancer cell growth. Breast cancer cells with IFI6 inhibition displayed similar phenotypes as those with UBE2T inhibition, and ectopic IFI6 expression in UBE2T-knockdown breast cancer cells prevented DNA replication stress and apoptosis and partly restored breast cancer cell growth. Furthermore, UBE2T inhibition enhanced the growth-suppressive effects of DNA replication stress inducers. Taken together, our study identifies UBE2T as a facilitator of breast cancer tumor growth and provide a rationale for targeting UBE2T for breast cancer therapies.