When to Consider Lynch Syndrome in Non-Colon and Non-Endometrial Malignancies.

Lynch syndrome (LS) is a common genetic syndrome characterized by pathogenic mutations of DNA mismatch repair genes resulting in a hereditary predisposition to cancer. While typically associated with colonic and endometrial cancer, LS additionally influences the development of many other malignancies. The Amsterdam II and Revised Bethesda Guidelines are the established clinical criteria for diagnosing LS. These guidelines are based on the most general characteristics of LS and do not address specific characteristics of the less commonly LS-associated malignancies. For individuals that present initially with a non-colon and non-endometrial malignancy, recommendations and guidelines on when to consider screening for LS are limited. Therefore, it is essential that clinicians are familiar with distinct LS-associated patient- and tumor-specific characteristics, especially of the less common LS-associated cancers, so that LS's diagnosis is not missed. In this review article, we focus on extra-colonic and extra-endometrial LS-associated cancers, paying particular attention to any established or currently investigated cancer features that help raise suspicion for LS and potentially lead to its earlier diagnosis. This review will also discuss current guidelines specific to each LS-associated malignancy.

Reporting Subclonal Immunohistochemical Staining of Mismatch Repair Proteins in Endometrial Carcinoma in the Times of Ever-Changing Guidelines.

CONTEXT.­: The current College of American Pathologists reporting guideline for mismatch repair protein (MMRP) immunohistochemistry for Lynch syndrome (LS) screening considers the presence of any positive nuclear staining as intact MMRP expression. This would include tumors with combined areas of subclonal retention and loss of MMRP staining. OBJECTIVE.­: To evaluate the clinical significance of reporting subclonal staining patterns of MMRP immunohistochemistry in endometrial carcinoma. DESIGN.­: We retrospectively reviewed 455 consecutive MMRP immunohistochemistry results of endometrial carcinoma in hysterectomy specimens from 2012 through 2017 and identified cases with subclonal MMRP staining. These results were correlated with the patient's personal and family history of LS-associated carcinoma, MLH1 promoter methylation status, and LS genetic testing. RESULTS.­: Subclonal staining of MMRP was seen in 48 of 455 cases (10.5%) on review. Thirty cases demonstrated isolated subclonal staining and were reported by pathologists as follows: subclonal (n = 5), complete MMRP loss (n = 4), and intact MMRP (n = 21). Eighteen cases had subclonal staining in combination with complete loss of other MMRP. Cases reported as subclonal or complete MMRP loss had appropriate clinical follow-up. Two of 2 cases with isolated subclonal MSH6 loss tested positive for LS. One of 3 cases with isolated subclonal MLH1/PMS2 loss was negative for MLH1 promoter methylation; LS genetic testing was not performed because of cost. CONCLUSIONS.­: Our study reveals that LS germline mutation can be detected in endometrial carcinoma patients whose tumors display sole subclonal MMRP staining. Our results stress the importance of reporting subclonal staining patterns to ensure appropriate clinical follow-up.

Adenosquamous carcinoma of the breast, an uncommon diagnosis with poor prognosis-Lessons learned from a 12-year analysis of the National Cancer Database.

We compared the clinicopathologic characteristics and prognosis of adenosquamous carcinoma (ASQ) of the breast with invasive ductal carcinoma (IDC), utilizing the National Cancer Database (NCDB) from 2004 to 2015. 1 932 688 female patients had invasive breast carcinoma; 1 421 250 had IDC (73.5%); and 453 had ASQ (0.0002%). When compared to IDC, ASQ patients were significantly (P < .05) older and had grade 1 tumors; negative lymph nodes; ER/PR/HER2-negative tumors; and worse 5-year overall survival (64.9% vs 74%, respectively). Our study, largest to date on ASQ, revealed an aggressive carcinoma with a significantly worse prognosis than IDC. "Personalized medicine" treatment approach for patients with this uncommon carcinoma is needed.

Nomogram update based on TAILORx clinical trial results - Oncotype DX breast cancer recurrence score can be predicted using clinicopathologic data.

OBJECTIVES: Oncotype DX (ODX), 21-gene breast cancer (BC) assay, predicts risk of recurrence and benefits of addition of chemotherapy to hormonal therapy for early-stage BC. We previously published a nomogram/calculator that could predict ODX results without performing the test by using clinicopathologic characteristics of BC available from pathology reports. Patients with intermediate-risk (11-25) ODXRS (RS) were excluded from that nomogram. This update tests the predictive value of clinicopathologic variables for forecasting the ODXRS while including intermediate-risk-ODXRS patients and stratifying ODXRS based on recently published TAILORx clinical trial results (0-25 = low-risk, 26-100 = high-risk-ODXRS; intermediate-risk-ODXRS belongs to the low-risk category). MATERIAL AND METHODS: The nomogram was built on 65,754 ODX-tested ER+/HER2-/lymph-node-negative patients with 6-50 mm tumor, captured by the National Cancer Data Base (NCDB) from 2010 to 2014. Five clinicopathologic variables (age, tumor size, grade, progesterone-receptor status (PR) and BC-histologic type) were assessed with logistic regression to predict for a low-risk (0-25) or a high-risk (26-100) ODXRS. Results were validated on a separate 18,585 ODX-tested cohort from 2015. RESULTS: Grade and PR were the highest significant predictors of both low-risk and high-risk-ODXRS, followed by histologic type, tumor size and age. The Receiver Operator Characteristic (ROC) curve showed strong statistical model for both low-risk and high-risk-ODXRS prediction outcomes (c-index = 0.81). CONCLUSIONS: An updated nomogram is now developed/validated on the entire population of ODX-tested patients (84,339) captured by the NCDB. The nomogram/calculator, available on-line at the UTMCK/Shiny website (https://utgsm.shinyapps.io/OncotypeDXCalculator/), will continue serving as a surrogate for BC patients for which ODX testing is not affordable, available or necessary.

Oncotype DX breast cancer recurrence score can be predicted with a novel nomogram using clinicopathologic data.

PURPOSE: Oncotype DX (ODX) recurrence score (RS) breast cancer (BC) assay is costly, and performed in only ~1/3 of estrogen receptor (ER)-positive BC patients in the USA. We have now developed a user-friendly nomogram surrogate prediction model for ODX based on a large dataset from the National Cancer Data Base (NCDB) to assist in selecting patients for which further ODX testing may not be necessary and as a surrogate for patients for which ODX testing is not affordable or available. METHODS: Six clinicopathologic variables of 27,719 ODX-tested ER+/HER2-/lymph node-negative patients with 6-50 mm tumor size captured by the NCDB from 2010 to 2012 were assessed with logistic regression to predict high-risk or low-risk ODXRS test results with TAILORx-trial and commercial cut-off values; 12,763 ODX-tested patients in 2013 were used for external validation. The predictive accuracy of the regression model was yielded using a Receiver Operator Characteristic analysis. Model fit was analyzed by plotting the predicted probabilities against the actual probabilities. A user-friendly calculator version of nomograms is available online at the University of Tennessee Medical Center website (Knoxville, TN). RESULTS: Grade and progesterone receptor status were the highest predictors of both low-risk and high-risk ODXRS, followed by age, tumor size, histologic tumor type and lymph-vascular invasion (C-indexes-.0.85 vs. 0.88 for TAILORx-trial vs. commercial cut-off values, respectively). CONCLUSION: This is the first study of this scale showing confidently that clinicopathologic variables can be used for prediction of low-risk or high-risk ODXRS using our nomogram models. These novel nomograms will be useful tools to help physicians and patients decide whether further ODX testing is necessary and are excellent surrogates for patients for which ODX testing is not affordable or available.

Evolving Trends and Influencing Factors in Mastectomy Decisions.

It is known that survival is unaffected by the choice of surgical management for breast cancer (BC) patients. Despite this fact, recent literature reveals that the number of bilateral mastectomies (BMs) in the United States is increasing. In an effort to elucidate potential factors influencing this trend, we investigated socioeconomic and clinicopathologic characteristics of our patient cohort that could have affected a patient's decision between unilateral mastectomy (UM) versus BM. Five-hundred-eight patients with unilateral BC who underwent mastectomy between 2000 and 2009 were analyzed: 397-UM; 111-BM. Influence of patient's age, insurance status, residence (rural versus urban), subsequent reconstruction, marital status, smoking history, family cancer history, cancer stage and grade on the BM versus UM patient's decision were analyzed using independent sample t tests, χ2 and logistic regression analysis. BM was more likely to be chosen by younger (<50 years) patients (P < 0.001); patients with private insurance [odds ratio (OR) = 2.22, 95% confidence interval (CI) = 1.4-3.5]; residence in urban settings (OR = 5.09, 95% CI = 2.5-10.4); and plans for subsequent reconstruction (OR = 2.31, 95% CI = 1.4-3.8). Marital status, smoking history, family cancer history, BC stage and grade did not significantly impact patient's choice of BM versus UM. We found that patients with unilateral BC who are younger (<50 year) have private insurance, reside in urban settings, or plan for subsequent reconstruction are more likely to undergo BM for unilateral BC. Genetic specific data were not evaluated for this patient cohort, and will be the subject of future analysis.

Utilization and impact of 21-gene recurrence score assay for breast cancer in clinical practice across the United States: lessons learned from the 2010 to 2012 National Cancer Data Base analysis.

The aim of our study is to investigate patient selection for the 21-gene recurrence score assay (RS) for breast cancer (BC) and the RS impact on chemotherapy administration (Chemo) in clinical practice across the United States through the retrospective observational study of National Cancer Data Base (NCDB) patients from 2010 to 2012. NCDB captures ~70 % of all newly diagnosed malignancies in the USA annually. The 2010-2012 period depicts data from the beginning of the NCDB that required recording of molecular assays and their data release in April 2015. De-identified demographic and clinical variables of patients that had RS results were analyzed. 513,080 patients had BC; 406,525 were estrogen receptor-positive (ER+). 74,334/91,651 patients with RS recorded as a numerical value (0-100) were analyzed (18.2 % of ER+). Patients' ages ranged from 18 to 90 (mean = 58.8, median = 59); 99.1 % were females. Patients of Caucasian race, from regions with <7 % having no high school education, and >$63,000 median household income were more likely to be tested than patients of other races, education, or income (p < 0.001). 58.1 % of tests were performed in ER+/lymph node-negative/>1 cm tumors; 16.4 % included ≥N1 disease; 9.9 % included T1a, T3, Stage III and IV, or HER2-positive cancers. Low-risk RS result had 92.2 % negative predictive value for no Chemo. Intermediate-risk RS result had 40.1 % positive predictive value (PPV); high-risk RS had 81.2 % PPV for Chemo. RS is obtained in ~1/5 of ER + BC patients across the USA. Further studies investigating influence and implementation of the newest evidence-based management guidelines regarding patients' selection for RS test and chemotherapy administration upon obtaining of test results are warranted.

Breast Cancer in Elderly Caucasian Women-An Institution-Based Study of Correlation between Breast Cancer Prognostic Markers, TNM Stage, and Overall Survival.

There is still a paucity of data on how breast cancer (BC) biology influences outcomes in elderly patients. We evaluated whether ER/PR/HER2 subtype and TNM stage of invasive BC had a significant impact on overall survival (OS) in a cohort of 232 elderly Caucasian female patients (≥70 year old (y/o)) from our institution over a ten-year interval (January 1998-July 2008). Five ER/PR/HER2 BC subtypes classified per 2011 St. Gallen International Expert Consensus recommendations were further subclassified into three subtypes (traditionally considered "favorable" subtype-ER+/PR+/HER2-, and traditionally considered "unfavorable" BC subtypes: HER2+ and triple negative). OS was measured comparing these categories using Kaplan Meier curves and Cox regression analysis, when controlled for TNM stage. The majority of our patients (178/232 = 76.8%) were of the "favorable" BC subtype; 23.2% patients were with "unfavorable" subtype (HER2+ = 12% (28/232) and triple negative = 11.2% (26/232)). Although a trend for better OS was noted in HER2+ patients (68%) vs. 56% in ER+/PR+ HER2- or 58% in triple negative patients, "favorable" BC subtype was not significantly predictive of better OS (p = 0.285). TNM stage was predictive of OS (p < 0.001). These results are similar to our published studies on Caucasian BC patients of all ages in which ER/PR/HER2 status was not predictive of OS, irrespective of classification system used.

Is the TNM staging system for breast cancer still relevant in the era of biomarkers and emerging personalized medicine for breast cancer - an institution's 10-year experience.

We have previously demonstrated that TNM status and age were significant predictors of overall survival (OS) in our study population of Caucasian patients with invasive breast carcinoma (2000-2004 study period). However, estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) biomarker expression was not predictive of OS when using the five-group ER/PR/HER2 subtype classification system recommended by St. Gallen International Consensus Panel in 2011. The current study reassessed the relevance of tumor biomarkers (ER/PR/HER2) in our study population using a recently proposed biologic TNM (bTNM) classification system in which the inclusion of triple negative ER/PR/HER2 phenotype (TNP) could improve the prognostic accuracy of TNM for staging, prognosis and treatment of breast cancer patients. Seven hundred eighty-two Caucasian women diagnosed with invasive ductal carcinoma from 1998 to 2008 were grouped according to their TNM stage and TNP versus non-TNP ER/PR/HER2 phenotype. OS was measured comparing these categories using Kaplan Meier curves and Cox regression analysis. TNM stage (Stage II = HR 1.41, 95% CI 1.01-1.97; Stage III = HR 3.96, 95% CI 2.68-5.88; Stage IV = HR 27.25, 95% CI 16.84-44.08), and age (HR 1.05, 95% CI 1.04-1.06) were significant predictors of OS. TNP significantly worsened prognosis/survival only in higher TNM stages (Stage III = HR 3.08, 95% CI 1.88-5.04, Stage IV = HR 24.36, 95% CI 13.81-42.99), but not in lower stages (I and II). Our data support the traditional TNM staging as a continued relevant predictive tool for breast cancer outcomes and show that biomarkers primarily improve the accuracy of TNM staging in advanced stages of breast cancer. We suspect that type of ER/PR/HER2 classification system(s) (St. Gallen, TNP, etc.), characteristics of populations studied (Caucasians, minorities, etc.), and the time period chosen for a study are major factors that determine impact of biomarkers on the prognostic accuracy of TNM. We propose systematic analyses of these factors before biomarkers are fully incorporated into the TNM staging system (bTNM).

Prognostic value of breast cancer subtypes, Ki-67 proliferation index, age, and pathologic tumor characteristics on breast cancer survival in Caucasian women.

Estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor receptor 2 (HER2) status are well-established prognostic markers in breast cancer management. The triple negative breast carcinoma subtype (ER-/PR-/HER2-) has been associated with worse overall prognosis in comparison with other subtypes in study populations consisting of ethnic minorities and young women. We evaluated the prognostic value of breast cancer subtypes, Ki-67 proliferation index (Ki-67PI), and pathologic tumor characteristics on breast cancer survival in Caucasian women in our institution, where greater than 90% of the total patient population is white. From 628 new invasive breast cancer cases in our data base (2000-late 2004), 593 (94%) were identified in Caucasian women. ER/PR/HER2 breast cancer subtypes were classified based on St. Gallen International Expert Consensus recommendations from 2011. ER/PR/HER2 status and its effect on survival were analyzed using a Kaplan-Meier curve. ER/PR/HER2 status, grade, tumor-node-metastasis status (TNM)/anatomic stage, and age were analyzed in terms of survival in a multivariate fashion using a Cox regression. Ki-67PI was analyzed between ER/PR/HER2 groups using the Kruskal-Wallis, Mann-Whitney U-tests, and 2 × 5 ANOVA. Our results showed that patients with stage IIB through stage IV breast carcinomas were 2.1-16 times more likely to die than patients with stages IA-B and IIA disease, respectively (95% CI 1.17-3.81 through 9.68-28.03, respectively), irrespective of ER/PR/HER2 subtype. Similar effect was seen with T2, N2/N3, or M1 tumors in comparison with T1, N0/N1, and M0 tumors. Chances of dying increase approximately 5% for every year increase in age. There was a significant main effect of Ki-67PI between ER/PR/HER2 subtypes, p < .001, but Ki-67PI could not predict survival. In summary, TNM status/anatomic stage of breast carcinomas and age are predictive of survival in our patient population of Caucasian women, but breast carcinoma subtypes and Ki-67 proliferation index are not.

Predictors of lymph node metastasis in T1 breast carcinoma, stratified by patient age.

It is important to identify T1-substage breast carcinomas (BCs) which are inherently aggressive, so that these can be managed more assertively. The purpose of this study was to distinguish those T1 BCs with the potential to metastasize to axillary lymph nodes from those lacking that ability by multiparametric analysis of several clinicopathologic features. The authors studied 197 patients with invasive BC who had undergone modified radical mastectomy; 161 tumors were ductal and 26 were lobular BCs. The study group was stratified by age into two groups:

Nup88 (karyoporin) in human malignant neoplasms and dysplasias: correlations of immunostaining of tissue sections, cytologic smears, and immunoblot analysis.

Nuclear pore complexes (NPCs) are elaborate macromolecular structures that regulate the bidirectional nucleocytoplasmic traffic system. In vertebrate cells, NPCs include a family of 50 to 100 proteins termed nucleoporins (Nups). The 88-kD Nup has been found to be linked in a dynamic subcomplex with the oncogenic CAN/Nup214. Applying a polyclonal antiserum to Nup88 on paraffin sections, we found that it immunoreacts with numerous malignant neoplasms. All carcinomas reacted irrespective of site, type, or degree of differentiation; often, high-grade carcinomas stained more strongly and extensively. Some sarcomas (e.g., fibrosarcomas, leiomyosarcomas, liposarcomas, and rhabdomyosarcomas) reacted intensely; melanomas, gliomas, mesotheliomas, and malignant lymphomas also stained. In situ carcinomas of the colon, stomach, breast, and prostate stained convincingly, as did in situ melanomas; some samples of fetal tissues also reacted. Cytologic smears of some of the aforementioned tumors also stained. In selected samples, enhanced immunostaining of tissue sections and cytologic smears correlated strongly and consistently with immunoblot data. Immunoblots of the same tumors with antibodies to 2 other Nups (Nup214 and Nup153) showed no comparable enhancement. Therefore, it seems that in some malignant tumors, Nup88 overexpression is not parallelled by an overexpression of other Nups. Benign tumors, hyperplasias, and normal tissues showed weak and sporadic staining or absence of staining; immunoblots of the same samples yielded weak signals. Occasional highly proliferative hyperplastic-reactive processes showed focal staining. Thus, our correlative histologic, cytologic, and molecular data indicate that Nup88 may be viewed as a potentially useful, broadly based histodiagnostic and molecular marker of many malignancies and premalignant dysplasias, and further suggest that in some malignant tumors, Nup88 may be selectively overexpressed as compared with other Nups. Thus, we propose that Nup88 be designated as karyoporin.