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Background: Perineuriomas of the gastrointestinal tract are benign neoplasms that commonly develop in the distal colon and are identified during screening colonoscopy; however, perineuriomas of the stomach are exceedingly rare and less frequently identified. Differentiating gastric perineuriomas from other more serious gastric neoplasms is critical to avoid unnecessarily aggressive treatments. Thus far, only six patients with gastric perineurioma have been described, and the molecular characterization of this entity is still lacking., Case Presentation: We report a 52-year-old woman who presented with abdominal pain and gastric acid reflux and was found to have a 1.5 cm subepithelial gastric neoplasm composed of bland spindle cells displacing the gastric glands with no cytologic atypia or mitotic activity, suggesting a benign spindle cell neoplasm. Immunohistochemical analysis showed reactivity for perineurial markers glucose transporter-1 and epithelial membrane antigen, consistent with benign gastric perineurioma. DNA extracted from the tissue was used for a capture-based target sequence enrichment panel followed by Illumina next-generation sequencing and targeted bioinformatic analysis for oncogenic alterations within defined disease-associated target regions. No sequence variants in the BRAF gene were identified., Conclusions: This rare case of gastric perineurioma helps solidify our understanding of how to discern various types of gastric neoplasms through traditional laboratory analysis alongside genetic sequencing approaches. Although extremely rare, gastric perineurioma should be kept in the differential diagnosis when assessing spindle cell gastric tumors to avoid unnecessary therapies, and physicians should understand the molecular characteristics of benign versus malignant tumors., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

This paper is a cross fertilization of ideas about the importance of molecular aspects of breast cancer metastasis by basic scientists, a pathologist, and clinical oncologists at the Henry Ford Health symposium. We address four major topics: (i) the complex roles of lymphatic endothelial cells and the molecules that stimulate them to enhance lymph node and systemic metastasis and influence the anti-tumor immunity that might inhibit metastasis; (ii) the interaction of molecules and cells when breast cancer spreads to bone, and how bone metastases may themselves spread to internal viscera; (iii) how molecular expression and morphologic subtypes of breast cancer assist clinicians in determining which patients to treat with more or less aggressive therapies; (iv) how the outcomes of patients with oligometastases in breast cancer are different from those with multiple metastases and how that could justify the aggressive treatment of these patients with the hope of cure., (© 2023. The Author(s), under exclusive licence to Springer Nature B.V.)

Backround: Inflammation characterized by the presence of T and B cells is often observed in prostate cancer, but it is unclear how T- and B-cell levels change during carcinogenesis and whether such changes influence disease progression., Methods: The study used a retrospective sample of 73 prostate cancer cases (45 whites and 28 African Americans) that underwent surgery as their primary treatment and had a benign prostate biopsy at least 1 year before diagnosis. CD3+, CD4+, and CD20+ lymphocytes were quantified by immunohistochemistry in paired pre- and post-diagnostic benign prostate biopsy and tumor surgical specimens, respectively. Clusters of similar trends of expression across two different timepoints and three distinct prostate regions-benign biopsy glands (BBG), tumor-adjacent benign glands (TAG), and malignant tumor glandular (MTG) regions-were identified using Time-series Anytime Density Peaks Clustering (TADPole). A Cox proportional hazards model was used to estimate the hazard ratio (HR) of time to biochemical recurrence associated with region-specific lymphocyte counts and regional trends., Results: The risk of biochemical recurrence was significantly reduced in men with an elevated CD20+ count in TAG (HR = 0.81, p = 0.01) after adjusting for covariates. Four distinct patterns of expression change across the BBG-TAG-MTG regions were identified for each marker. For CD20+, men with low expression in BBG and higher expression in TAG compared to MTG had an adjusted HR of 3.06 (p = 0.03) compared to the reference group that had nominal differences in CD20+ expression across all three regions. The two CD3+ expression patterns that featured lower CD3+ expression in the BBG compared to the TAG and MTG regions had elevated HRs ranging from 3.03 to 4.82 but did not reach statistical significance., Conclusions: Longitudinal and spatial expression patterns of both CD3+ and CD20+ suggest that increased expression in benign glands during prostate carcinogenesis is associated with an aggressive disease course., (© 2024 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent., Significance: Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race-group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Telomere shortening is linked to aging and may be associated with increased risk for cancer. Most cancer studies have used telomere length in leukocytes rather than in the target tissue of cancer origin., Methods: A case-control study of 524 case-control pairs with a benign prostate biopsy nested within a historical cohort of 10,478 men was conducted to determine whether premalignant prostate telomere length (assessed using a modified qRT-PCR) is associated with prostate cancer risk., Results: Telomere lengths in benign prostate biopsies of cases versus controls were similar (1.46 ± 0.38 vs. 1.45 ± 0.42; P = 0.49). African American (AA) men had significantly shorter telomeres compared with White men (1.51 ± 0.38 vs. 1.63 ± 0.39; P < 0.0001). In race-stratified analyses, increasing telomere length was more strongly associated with prostate cancer risk in White men, wherein those with telomere length in the highest quartile had 1.9-fold greater adjusted risk of prostate cancer compared with men with prostate telomere lengths in the lowest quartile [OR = 1.90; 95% confidence interval (CI) = 1.08-3.36]. Men in the highest telomere length quartile also had a greater risk of aggressive prostate cancer compared with men with telomere lengths in the lowest quartile (OR = 2.78; 95% CI = 1.25-6.19)., Conclusions: White men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease., Impact: Race-specific telomere length measures may be an early biomarker of aggressive prostate cancer., (©2022 American Association for Cancer Research.)

Background: The detection of somatic mutations in cell-free DNA (cfDNA) from liquid biopsy has emerged as a noninvasive tool to monitor the follow-up of cancer patients. However, the significance of cfDNA clinical utility remains uncertain in patients with brain tumors, primarily because of the limited sensitivity cfDNA has to detect real tumor-specific somatic mutations. This unresolved challenge has prevented accurate follow-up of glioma patients with noninvasive approaches., Methods: Genome-wide DNA methylation profiling of tumor tissue and serum cfDNA of glioma patients., Results: Here, we developed a noninvasive approach to profile the DNA methylation status in the serum of patients with gliomas and identified a cfDNA-derived methylation signature that is associated with the presence of gliomas and related immune features. By testing the signature in an independent discovery and validation cohorts, we developed and verified a score metric (the "glioma-epigenetic liquid biopsy score" or GeLB) that optimally distinguished patients with or without glioma (sensitivity: 100%, specificity: 97.78%). Furthermore, we found that changes in GeLB score reflected clinicopathological changes during surveillance (eg, progression, pseudoprogression, and response to standard or experimental treatment)., Conclusions: Our results suggest that the GeLB score can be used as a complementary approach to diagnose and follow up patients with glioma., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Systemic inflammation may increase risk for prostate cancer progression, but the role it plays in prostate cancer susceptibility is unknown. From a cohort of over 10,000 men who had either a prostate biopsy or transurethral resection that yielded a benign finding, we analyzed 517 incident prostate cancer cases identified during follow-up and 373 controls with one or more white blood cell tests during a follow-up period between one and 18 years. Multilevel, multivariable longitudinal models were fit to two measures of systemic inflammation, neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR), to determine NLR and MLR trajectories associated with increased risk for prostate cancer. For both measures, we found no significant differences in the trajectories by case/control status, however in modeling NLR trajectories there was a significant interaction between race (white or Black and case-control status. In race specific models, NLR and MLR values were consistently higher over time among white controls than white cases while case-control differences in NLR and MLR trajectories were not apparent among Black men. When cases were classified as aggressive as compared to non-aggressive, the case-control differences in NLR and MLR values over time among white men were most apparent for non-aggressive cases. For NLR among white men, significant case-control differences were observed for the entire duration of observation for men who had inflammation in their initial prostate specimen. It is possible that, among white men, monitoring of NLR and MLR trajectories after an initial negative biopsy may be useful in monitoring prostate cancer risk., Competing Interests: The authors have declared that no competing interests exist.

Growth and differentiation factor 15 (GDF-15), also known as macrophage inhibitory cytokine 1 (MIC-1), may act as both a tumor suppressor and promotor and, by regulating NF-κB and macrophage signaling, promote early prostate carcinogenesis. To determine whether expression of these two inflammation-related proteins affect prostate cancer susceptibility, dual immunostaining of benign prostate biopsies for GDF-15 and NF-κB was done in a study of 503 case-control pairs matched on date, age, and race, nested within a historical cohort of 10,478 men. GDF-15 and NF-κB expression levels were positively correlated (r = 0.39; p < 0.0001), and both were significantly lower in African American (AA) compared with White men. In adjusted models that included both markers, the odds ratio (OR) for NF-κB expression was statistically significant, OR =0.87; p = 0.03; 95% confidence interval (CI) =0.77-0.99, while GDF-15 expression was associated with a nominally increased risk, OR =1.06; p = 0.27; 95% CI =0.96-1.17. When modeling expression levels by quartiles, the highest quartile of NF-κB expression was associated with almost a fifty percent reduction in prostate cancer risk (OR =0.51; p = 0.03; 95% CI =0.29-0.92). In stratified models, NF-κB had the strongest negative association with prostate cancer in non-aggressive cases (p = 0.03), older men (p = 0.03), and in case-control pairs with longer follow-up (p = 0.02). Risk associated with GDF-15 expression was best fit using nonlinear regression modeling where both first (p = 0.02) and second (p = 0.03) order GDF-15 risk terms were associated with significantly increased risk. This modeling approach also revealed significantly increased risk associated with GDF-15 expression for subsamples defined by AA race, aggressive disease, younger age, and in case-control pairs with longer follow-up. Therefore, although positively correlated in benign prostatic biopsies, NF-κB and GDF-15 expression appear to exert opposite effects on risk of prostate tumor development., (© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

HER2 (ERBB2) gene status serves as a strong predictive marker of response to HER2-targeted agents in invasive breast cancers, albeit with heterogeneous response. Our aim was to determine the distribution and prognosis of HER2 groups by fluorescent in situ hybridization (FISH) using the updated 2018 American Society of Clinical Oncology-College of American Pathologist (ASCO-CAP) guidelines. We identified 226 cases of equivocal or positive HER2 FISH invasive breast cancer (interpreted by ASCO-CAP guidelines at the time of reporting) who received HER2-targeted agents from 2006 to 2017. We subcategorized Group 1 further into three subgroups: low amplified (HER2/CEP17 ratio ≥ 2.0-2.99, mean HER2/cell 4.0-5.9), amplified (HER2/CEP17 ratio ≥ 2.0-2.99, mean HER2/cell ≥ 6), and excessive amplification (HER2/CEP17 ratio ≥ 3.0, mean HER2/cell ≥ 4.0). Outcomes studied were recurrence, metastasis, second breast primary, disease-specific survival (DSS), and overall survival (OS). Univariate analysis showed that the five categories of HER2 FISH were significantly associated with OS (p < 0.01), specifically higher HER2 amplification was associated with fewer deaths. HER2 FISH status also statistically significantly relates to DFS (p < 0.01) and metastasis (p = 0.01) but not with recurrence or second breast primary in our study. Tumor type and HER2 ISH Groups are independent predictors for both OS and DFS in our cohort. The proposed Group 1 subcategories were significantly associated with OS (p < 0.01) and DFS (p < 0.01), excessive HER2 amplification was associated with longer median survival. The Cox regression models showed better survival outcomes for the excessive amplification subgroup than the low amplified subgroup, with OS (hazard ratio = 0.63, 95% CI 0.42-0.93) and DFS (HR = 0.55, 95% CI 0.37-0.83). We demonstrated that in HER2 FISH Group 1 patients, high HER2 amplification was significantly associated with longer OS and DFS; these patients seem to benefit more from HER2-targeted regimens. We recommend reporting these Group 1 subcategories when assessing HER2 FISH.

Aims: To evaluate the molecular underpinnings of the rare aggressive prostate cancer variants adenosquamous carcinoma, pleomorphic giant-cell carcinoma, and sarcomatoid carcinoma., Methods and Results: We retrieved 19 tumours with one or more variant(s), and performed ERG immunohistochemistry, a next-generation sequencing assay targeting recurrent gene fusions, and fluorescence in-situ hybridisation (FISH) for ERG and BRAF. Divergent differentiation included: sarcomatoid carcinoma (n = 10), adenosquamous carcinoma (n = 7), and pleomorphic giant-cell carcinoma (n = 7). Five patients had more than one variant. Four had variants only in metastases. ERG rearrangement was detected in nine (47%, seven via sequencing, showing TMPRSS2-ERG fusions and one GRHL2-ERG fusion, and two via FISH, showing rearrangement via deletion). ERG was immunohistochemically positive in the adenocarcinoma in eight of nine (89%) patients, but was immunohistochemically positive in the variant in only five of nine patients (56%, typically decreased). One patient had a false-positive ERG immunohistochemical result in the sarcomatoid component despite a negative FISH result. Two (11%) harboured BRAF fusions (FAM131A-BRAF and SND1-BRAF)., Conclusions: ERG fusions are present in these rare prostate cancer variants with a frequency close to that in conventional prostate cancer (9/19, 47%). ERG immunohistochemistry usually detects rearrangement in the adenocarcinoma, but is less sensitive for the variant histology, with weak to negative staining. Adenosquamous and sarcomatoid variants can, particularly, occur together. Molecular assessment may be an additional tool in selected cases to confirm the prostatic origin of unusual tumours. The presence of two BRAF rearrangements suggests that this gene fusion may be enriched in this setting, as RAF kinase fusions have been previously reported in 1-2% of prostate cancers., (© 2020 John Wiley & Sons Ltd.)

Cranial fasciitis is an uncommon benign fibroblastic tumor, generally histologically identical to nodular fasciitis. It develops almost exclusively in children. Cranial fasciitis manifests clinically as a painless rapidly growing solitary nodule in the head and neck area, frequently eroding the underlying bone. Thus, this entity is often confused with aggressive lesions such as sarcomas, both clinically and radiologically. Histopathologic examination is essential to differentiate between cranial fasciitis and fibrohistiocytic or even sarcomatous lesions observed in children. In this article, we present a case of cranial fasciitis with intracranial extension in a 2-year-old boy. Although USP6 rearrangement has recently been recognized as a recurring alteration in nodular fasciitis, we present a novel COL1A1-CAMTA1 fusion in this lesion.

Prostate cancer is frequently multifocal. Although there may be morphological variation, the genetic underpinnings of each tumor are not clearly understood. To assess the inter and intra tumor molecular heterogeneity in prostate biopsy samples, we developed a combined immunohistochemistry and RNA in situ hybridization method for the simultaneous evaluation of ERG, SPINK1, ETV1, and ETV4. Screening of 601 biopsy cores from 120 consecutive patients revealed multiple alterations in a mutually exclusive manner in 37% of patients, suggesting multifocal tumors with considerable genetic differences. Furthermore, the incidence of molecular heterogeneity was higher in African Americans patients compared with Caucasian American patients. About 47% of the biopsy cores with discontinuous tumor foci showed clonal differences with distinct molecular aberrations. ERG positivity occurred in low-grade cancer, whereas ETV4 expression was observed mostly in high-grade cancer. Further studies revealed correlation between the incidence of molecular markers and clinical and pathologic findings, suggesting potential implications for diagnostic pathology practice, such as defining dominant tumor nodules and discriminating juxtaposed but molecularly different tumors of different grade patterns.

M2 (tumor-supportive) macrophages may upregulate growth differentiation factor 15 (GDF15), which is highly expressed in prostate tumors, but the combined utility of these markers as prognostic biomarkers are unclear. We retrospectively studied 90 prostate cancer cases that underwent radical prostatectomy as their primary treatment and were followed for biochemical recurrence (BCR). These cases also had a benign prostate biopsy at least 1 year or more before their prostate cancer surgery. Using computer algorithms to analyze digitalized immunohistochemically stained slides, GDF15 expression and the presence of M2 macrophages based on the relative density of CD204- and CD68-positive macrophages were measured in prostate: (i) benign biopsy, (ii) cancer and (iii) tumor-adjacent benign (TAB) tissue. Both M2 macrophages (P = 0.0004) and GDF15 (P < 0.0001) showed significant inter-region expression differences. Based on a Cox proportional hazards model, GDF15 expression was not associated with BCR but, in men where GDF15 expression differences between cancer and TAB were highest, the risk of BCR was significantly reduced (hazard ratio = 0.26; 95% confidence interval = 0.09-0.94). In addition, cases with high levels of M2 macrophages in prostate cancer had almost a 5-fold increased risk of BCR (P = 0.01). Expression of GDF15 in prostate TAB was associated with M2 macrophage levels in both prostate cancer and TAB and appeared to moderate M2-macrophage-associated BCR risk. In summary, the relationship of GDF15 expression and CD204-positive M2 macrophage levels is different in a prostate tumor environment compared with an earlier benign biopsy and, collectively, these markers may predict aggressive disease., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDL) and spindle cell lipoma are lipomatous tumors with distinct clinical, molecular, and prognostic features. Although histological and immunophenotypic features can overlap between ALT/WDL and spindle cell lipoma, the oncogenesis and clinical behavior are markedly different. In borderline cases, molecular analysis for MDM2 or CDK4 amplification can aid in distinguishing ALT/WDL from spindle cell lipoma. Although dedifferentiated liposarcoma has been reported to harbor both MDM2 amplification and loss of the RB1 region, we are not aware of a reported RB1 loss in well-differentiated ALT/WDL. In this article, we present a 69-year-old woman with a lipomatous tumor in the gluteal region that histologically, immunohistochemically, and molecularly mimicked spindle cell lipoma (with positive immunohistochemical staining for CD34 and loss of the RB1 gene region), yet harbored amplification of MDM2 and CDK4 confirmed by fluorescence in situ hybridization, supporting classification as ALT/WDL. This case strengthens the argument that in atypical clinical contexts, molecular studies for MDM2/CDK4 should be considered in tumors resembling spindle cell lipoma.

Background: Expression profiles of erythroblast transformation-specific (ETS)-related gene fusions and serine protease inhibitor Kazal-type 1 (SPINK1) in early onset prostate cancer have not been thoroughly explored., Methods: We retrieved 151 radical prostatectomy specimens from young men with prostate cancer (<55 years) and characterized the expression of ETS-related gene (ERG), SPINK1, ETS Variant 1 (ETV1), and ETV4 by dual immunohistochemistry and dual RNA in situ hybridization. Age, race, family history, preoperative prostate-specific antigen, biochemical recurrence, and pathological variables using whole-mount radical prostatectomy tissue were collected., Results: A total of 313 tumor nodules from 151 men including 68 (45%) Caucasians and 61 (40%) African Americans were included in the analysis. Positive family history of prostate cancer was seen in 65 (43%) patients. Preoperative prostate-specific antigen ranged from 0.3 to 52.7 ng/mL (mean = 7.04). The follow-up period ranged from 1 to 123.7 months (mean = 30.3). Biochemical recurrence was encountered in 8 of 151 (5%). ERG overexpression was observed in 85 of 151 (56%) cases, followed by SPINK1 in 61 of 151 (40%), ETV1 in 9 of 149 (6%), and ETV4 in 4 of 141 (3%). There were 25 of 151 (17%) cases showing both ERG and SPINK1 overexpression within different regions of either the same tumor focus or different foci. Higher frequency of ERG overexpression was seen in younger patients (≤45 years old; 76% vs 49%, P = .002), Caucasian men (71% vs 41% P = .0007), organ-confined tumors (64% vs 33%, P = .0008), and tumors of Gleason Grade groups 1 and 2 (62% vs 26%, P = .009). SPINK1 overexpression was more in African American men (68% vs 26%, P = .00008), in tumors with high tumor volume (>20%) and with anterior located tumors. ETV1 and ETV4 demonstrated rare overexpression in these tumors, particularly in the higher-grade tumors., Conclusion: This study expands the knowledge of the clonal evolution of multifocal cancer in young patients and support differences in relation to racial background and genetics of prostate cancer., (© 2019 Wiley Periodicals, Inc.)

We present the functional characterization of a pseudogene associated recurrent gene fusion in prostate cancer. The fusion gene KLK4-KLKP1 is formed by the fusion of the protein coding gene KLK4 with the noncoding pseudogene KLKP1. Screening of a cohort of 659 patients (380 Caucasian American; 250 African American, and 29 patients from other races) revealed that the KLK4-KLKP1 is expressed in about 32% of prostate cancer patients. Correlative analysis with other ETS gene fusions and SPINK1 revealed a concomitant expression pattern of KLK4-KLKP1 with ERG and a mutually exclusive expression pattern with SPINK1, ETV1, ETV4, and ETV5. Development of an antibody specific to KLK4-KLKP1 fusion protein confirmed the expression of the full-length KLK4-KLKP1 protein in prostate tissues. The in vitro and in vivo functional assays to study the oncogenic properties of KLK4-KLKP1 confirmed its role in cell proliferation, cell invasion, intravasation, and tumor formation. Presence of strong ERG and AR binding sites located at the fusion junction in KLK4-KLKP1 suggests that the fusion gene is regulated by ERG and AR. Correlative analysis of clinical data showed an association of KLK4-KLKP1 with lower preoperative PSA values and in young men (<50 years) with prostate cancer. Screening of patient urine samples showed that KLK4-KLKP1 can be detected noninvasively in urine. Taken together, we present KLK4-KLKP1 as a class of pseudogene associated fusion transcript in cancer with potential applications as a biomarker for routine screening of prostate cancer., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Rising prostate-specific antigen (PSA) levels are associated with both increased risk of prostate cancer and prostatic inflammation. The confounding effects of inflammation on the utility of PSA kinetics to predict prostate cancer may be partially mitigated by anti-inflammatory drug use. We investigated the influence of anti-inflammatory drug use on the association of PSA kinetics with prostate cancer risk., Methods: We studied 488 prostate cancer case-control pairs (290 white, 198 African American (AA)) nested in a retrospective cohort of men with a benign prostate biopsy. A series of multivariable models estimated prostate cancer risk associated with PSA velocity (PSAV) at different levels of anti-inflammatory drug use while adjusting for the presence of both clinical and histologic prostatitis., Results: In men with one, two, or three or more courses of anti-inflammatory drug use, for each ng/mL/year increase in PSAV, prostate cancer risk increased 1.21-fold, 1.83-fold, and 1.97-fold, respectively ( P < 0.0001). In controls with histologic prostatitis, anti-inflammatory drug use was associated with a significantly lower PSAV ( P < 0.0001). This association was not observed in men with histologic prostatitis who were subsequently diagnosed with prostate cancer. A positive interaction between anti-inflammatory drug use and PSAV-associated prostate cancer risk was only observed in AA men, as well as a strong positive association between any anti-inflammatory drug use and clinical prostatitis ( P = 0.004)., Conclusions: In men with benign prostate biopsy, accounting for the presence of histologic prostatitis and anti-inflammatory drug use, particularly in AA men, may help distinguish between men with rising PSA because of prostatitis vs undiagnosed cancer., (© 2019 Wiley Periodicals, Inc.)

NF1 germline mutation predisposes to breast cancer. NF1 mutations have also been proposed as oncogenic drivers in sporadic breast cancers. To understand the genomic and histologic characteristics of these breast cancers, we analyzed the tumors with NF1 germline mutations and also examined the genomic and proteomic profiles of unselected tumors. Among 14 breast cancer specimens from 13 women affected with neurofibromatosis type 1 (NF1), 9 samples (NF + BrCa) underwent genomic copy number (CN) and targeted sequencing analysis. Mutations of NF1 were identified in two samples and TP53 were in three. No mutation was detected in ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50 , and STK11 HER2 (ErbB2) overexpression was detected by IHC in 69.2% (9/13) of the tumors. CN gain/amplification of ERBB2 was detected in 4 of 9 with DNA analysis. By evaluating HER2 expression and NF1 alterations in unselected invasive breast cancers in TCGA datasets, we discovered that among samples with ERBB2 CN gain/amplification, the HER2 mRNA and protein expression were much more pronounced in NF1 -mutated/deleted samples in comparison with NF1 -unaltered samples. This finding suggests a synergistic interplay between these two genes, potentially driving the development of breast cancer harboring NF1 mutation and ERBB2 CN gain/amplification. NF1 gene loss of heterozygosity was observed in 4 of 9 NF + BrCa samples. CDK4 appeared to have more CN gain in NF + BrCa and exhibited increased mRNA expression in TCGA NF1- -altered samples. Cancer Prev Res; 11(10); 655-64. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Aims: Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract have a debatable relationship with inflammatory myofibroblastic tumour (generally lacking ALK rearrangement); however, they share several overlapping features with nodular fasciitis of soft tissue. As rearrangement of the USP6 gene has been recently recognised as a recurrent alteration in soft tissue nodular fasciitis, and several other alternative gene fusions have been recently recognised in inflammatory myofibroblastic tumour, the aim of this study was to investigate whether USP6, ROS1 or ETV6 rearrangements were present in these lesions (12 cases)., Methods and Results: Fluorescence in-situ hybridisation analysis was performed by the use of bacterial artificial chromosome-derived break-apart probes against USP6, ROS1, and ETV6. Two cases with adequate genetic material from recent paraffin tissue blocks were also tested by use of a solid tumour gene fusion detection assay via next-generation sequencing, targeting >50 known genes involved in recurrent fusions. None of the genitourinary pseudosarcomatous myofibroblastic proliferations was found to harbour USP6 (0/12), ROS1 (0/8) or ETV6 (0/7) rearrangements, and no gene fusions were detected in two cases studied by sequencing., Conclusions: Despite overlap in histological and immunohistochemical features between pseudosarcomatous myofibroblastic proliferation and nodular fasciitis, these tumours lack the recently recognised USP6 rearrangements that occur in nodular fasciitis, as well as alternative fusions found in ALK-negative inflammatory myofibroblastic tumours. At present, this diagnosis remains based primarily on clinical, histological and immunohistochemical features., (© 2018 John Wiley & Sons Ltd.)

NF1 mutations predispose to neurofibromatosis type 1 (NF1) and women with NF1 have a moderately elevated risk for breast cancer, especially under age 50. Germline genomic analysis may better define the risk so screening and prevention can be applied to the individuals who benefit the most. Survey conducted in several neurofibromatosis clinics in the United States has demonstrated a 17.2% lifetime risk of breast cancer in women affected with NF1. Cumulated risk to age 50 is estimated to be 9.27%. For genomic profiling, fourteen women with NF1 and a history of breast cancer were recruited and underwent whole exome sequencing (WES), targeted genomic DNA based and RNA-based analysis of the NF1 gene. Deleterious NF1 pathogenic variants were identified in each woman. Frameshift mutations because of deletion/duplication/complex rearrangement were found in 50% (7/14) of the cases, nonsense mutations in 21% (3/14), in-frame splice mutations in 21% (3/14), and one case of missense mutation (7%, 1/14). No deleterious mutation was found in the following high/moderate-penetrance breast cancer genes: ATM, BRCA1, BRCA2, BARD1, BRIP1, CDH1, CHEK2, FANCC, MRE11A, NBN, PALB2, PTEN, RAD50, RAD51C, TP53, and STK11. Twenty-five rare or common variants in cancer related genes were discovered and may have contributed to the breast cancers in these individuals. Breast cancer predisposition modifiers in women with NF1 may involve a great variety of molecular and cellular functions., (© 2017 Wiley Periodicals, Inc.)

Clear cell renal cell carcinoma is by far the most common form of kidney cancer; however, a number of histologically similar tumors are now recognized and considered distinct entities. The Cancer Genome Atlas published data set was queried (http://cbioportal.org) for clear cell renal cell carcinoma tumors lacking VHL gene mutation and chromosome 3p loss, for which whole-slide images were reviewed. Of the 418 tumors in the published Cancer Genome Atlas clear cell renal cell carcinoma database, 387 had VHL mutation, copy number loss for chromosome 3p, or both (93%). Of the remaining, 27/31 had whole-slide images for review. One had 3p loss based on karyotype but not sequencing, and three demonstrated VHL promoter hypermethylation. Nine could be reclassified as distinct or emerging entities: translocation renal cell carcinoma (n=3), TCEB1 mutant renal cell carcinoma (n=3), papillary renal cell carcinoma (n=2), and clear cell papillary renal cell carcinoma (n=1). Of the remaining, 6 had other clear cell renal cell carcinoma-associated gene alterations (PBRM1, SMARCA4, BAP1, SETD2), leaving 11 specimens, including 2 high-grade or sarcomatoid renal cell carcinomas and 2 with prominent fibromuscular stroma (not TCEB1 mutant). One of the remaining tumors exhibited gain of chromosome 7 but lacked histological features of papillary renal cell carcinoma. Two tumors previously reported to harbor TFE3 gene fusions also exhibited VHL mutation, chromosome 3p loss, and morphology indistinguishable from clear cell renal cell carcinoma, the significance of which is uncertain. In summary, almost all clear cell renal cell carcinomas harbor VHL mutation, 3p copy number loss, or both. Of tumors with clear cell histology that lack these alterations, a subset can now be reclassified as other entities. Further study will determine whether additional entities exist, based on distinct genetic pathways that may have implications for treatment.

Background: Obesity is associated with risk of aggressive prostate cancer (PCa), but not with over-all PCa risk. However, obese men have larger prostates which may lower biopsy accuracy and cause a systematic bias toward the null in epidemiologic studies of over-all risk., Methods: Within a cohort of 6692 men followed-up after a biopsy or transurethral resection of the prostate (TURP) with benign findings, a nested case-control study was conducted of 495 prostate cancer cases and controls matched on age, race, follow-up duration, biopsy versus TURP, and procedure date. Data on body mass index and prostate volume at the time of the initial procedure were abstracted from medical records., Results: Prior to consideration of differences in prostate volume, overweight (OR = 1.41; 95%CI 1.01, 1.97), and obese status (OR = 1.59; 95%CI 1.09, 2.33) at the time of the original benign biopsy or TURP were associated with PCa incidence during follow-up. Prostate volume did not significantly moderate the association between body-size and PCa, however it did act as an inverse confounder; adjustment for prostate volume increased the effect size for overweight by 22% (adjusted OR = 1.52; 95%CI 1.08, 2.14) and for obese status by 23% (adjusted OR = 1.77; 95%CI 1.20, 2.62). Larger prostate volume at the time of the original benign biopsy or TURP was inversely associated with PCa incidence during follow-up (OR = 0.92 per 10 cc difference in volume; 95%CI 0.88, 0.97). In analyses that stratified case-control pairs by tumor aggressiveness of the case, prostate volume acted as an inverse confounder in analyses of non-aggressive PCa but not in analyses of aggressive PCa., Conclusions: In studies of obesity and PCa, differences in prostate volume cause a bias toward the null, particularly in analyses of non-aggressive PCa. A pervasive underestimation of the association between obesity and overall PCa risk may exist in the literature., (© 2017 Wiley Periodicals, Inc.)

Amplification of chromosome 6p has been implicated in aggressive behavior in several cancers, but has not been characterized in renal cell carcinoma (RCC). We identified 9 renal tumors with amplification of chromosome 6p including the TFEB gene, 3 by fluorescence in situ hybridization, and 6 from the Cancer Genome Atlas (TCGA) databases. Patients' ages were 28 to 78 years (median, 61 y). Most tumors were high stage (7/9 pT3a, 2/9 pN1). Using immunohistochemistry, 2/4 were positive for melanocytic markers and cathepsin K. Novel TFEB fusions were reported by TCGA in 2; however, due to a small composition of fusion transcripts compared with full-length transcripts (0.5/174 and 3.3/132 FPKM), we hypothesize that these represent secondary fusions due to amplification. Five specimens (4 TCGA, 1 fluorescence in situ hybridization) had concurrent chromosome 3p copy number loss or VHL deletion. However, these did not resemble clear cell RCC, had negative carbonic anhydrase IX labeling, lacked VHL mutation, and had papillary or unclassified histology (2/4 had gain of chromosome 7 or 17). One tumor each had somatic FH mutation and SMARCB1 mutation. Chromosome 6p amplification including TFEB is a previously unrecognized cytogenetic alteration in RCC, associated with heterogenous tubulopapillary eosinophilic and clear cell histology. The combined constellation of features does not fit cleanly into an existing tumor category (unclassified), most closely resembling papillary or translocation RCC. The tendency for high tumor stage, varied tubulopapillary morphology, and a subset with melanocytic marker positivity suggests the possibility of a unique tumor type, despite some variation in appearance and genetics.

Background: Breast cancer sentinel lymph nodes (SLNs) with metastases (mets) are often palpably enlarged. We hypothesized that the volume of the SLN and the size of mets are directly related. SLNs harboring mets are often firm, with increased intra-nodal pressure (INP), and we hypothesized that SLN volume, as well as INP, would correlate directly with SLN metastasis size., Methods: The SLN volume, INP and met size were measured in 296 SLNs and compared using linear regression analysis. The SLNs were subsequently grouped based upon pN stage. SLN INP and volume were compared between these resultant groups., Results: Increased SLN volume significantly predicted increased SLN met size on univariate and multivariate analysis (p = 0.001 and p = 0.011, respectively). SLN met size predicted increased SLN INP on both univariate and multivariate analysis (both p = 0.001). SLN volume only significantly correlated with increased SLN INP on univariate analysis (p = 0.001). On subgroup analysis of nodal disease, pN1/2/3 nodes (SLN met sizes >2 mm) were significantly larger (p = 0.039 and p = 0.003, respectively) than pN0 and pN1(mi) nodes, and had significantly increased INP (all p = 0.001) as compared to pN0, pN0(i+), and pN1(mi) nodes., Conclusions: SLN volume and INP increased with increasing SLN met size. The threshold met size for this increase was >2 mm (pN1 disease)., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

In DNA from prostate tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue--prior to malignant transformation--may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received "definitive" treatment [radical prostatectomy (58%) or radiation therapy (42%)]. Cases were drawn from a large hospital-based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time-to-event analyses. Average follow-up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23-4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51-8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07-13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease., (© 2016 UICC.)

Background: Epidemiologic studies, primarily done in white men, suggest that a history of clinically-diagnosed prostatitis increases prostate cancer risk, but that histological prostate inflammation decreases risk. The relationship between a clinical history of prostatitis and histologic inflammation in terms of how these two manifestations of prostatic inflammation jointly contribute to prostate cancer risk and whether racial differences exist in this relationship is uncertain., Methods: Using a nested design within a cohort of men with benign prostate tissue specimens, we analyzed the data on both clinically-diagnosed prostatitis (NIH categories I-III) and histological inflammation in 574 prostate cancer case-control pairs (345 white, 229 African American)., Results: Clinical prostatitis was not associated with increased prostate cancer risk in the full sample, but showed a suggestive inverse association with prostate cancer in African Americans (odds ratio (OR)=0.47; 95% confidence interval (CI)=0.27-0.81). In whites, clinical prostatitis increased risk by 40%, but was only associated with a significant increased prostate cancer risk in the absence of evidence of histological inflammation (OR=3.56; 95% CI=1.15-10.99). Moreover, PSA velocity (P=0.008) and frequency of PSA testing (P=0.003) were significant modifiers of risk. Clinical prostatitis increased risk of prostate cancer almost three-fold (OR=2.97; 95% CI=1.40-6.30) in white men with low PSA velocity and about twofold in white men with more frequent PSA testing (OR=1.91; 95% CI=1.09-3.35)., Conclusions: In our cohort of men with benign prostate specimens, race, and histological inflammation were important cofactors in the relationship between clinical prostatitis and prostate cancer. Clinical prostatitis was associated with a slightly decreased risk for prostate cancer in African American men. In white men, the relationship between clinical prostatitis and prostate cancer risk was modified by histological prostatic inflammation, PSA velocity, and frequency of PSA testing-suggesting a complex interplay between these indications of prostatic inflammation and prostate cancer detection.

Consumption of cruciferous vegetables is associated with a decreased risk of developing prostate cancer. Antineoplastic effects of cruciferous vegetables are attributable to bioactive indoles, most prominently, 3, 3'-diindolylmethane (DIM). In addition to effects on proliferation and apoptosis, DIM acts as an antiandrogen in prostate cancer cell lines. This study characterized the effects of prostatic DIM on the androgen receptor (AR) in patients with prostate cancer. Men with localized prostate cancer were treated with a specially formulated DIM capsule designed for enhanced bioavailability (BR-DIM) at a dose of 225 mg orally twice daily for a minimum of 14 days. DIM levels and AR activity were assessed at the time of prostatectomy. Out of 28 evaluable patients, 26 (93%) had detectable prostatic DIM levels, with a mean concentration of 14.2 ng/gm. The mean DIM plasma level on BR-DIM therapy was 9.0 ng/mL; levels were undetectable at baseline and in follow-up samples. AR localization in the prostate was assessed with immunohistochemistry. After BR-DIM therapy, 96% of patients exhibited exclusion of the AR from the cell nucleus. In contrast, in prostate biopsy samples obtained prior to BR-DIM therapy, no patient exhibited AR nuclear exclusion. Declines in PSA were observed in a majority of patients (71%). Compliance was excellent and toxicity was minimal. In summary, BR-DIM treatment resulted in reliable prostatic DIM levels and anti-androgenic biologic effects at well tolerated doses. These results support further investigation of BR-DIM as a chemopreventive and therapeutic agent in prostate cancer.

Sarcoidosis is a complex, multi-organ granulomatous disease with a likely genetic component. West African ancestry confers a higher risk for sarcoidosis than European ancestry. Admixture mapping provides the most direct method to locate genes that underlie such ethnic variation in disease risk. We sought to identify genetic risk variants within four previously-identified ancestry-associated regions-6p24.3-p12.1, 17p13.3-13.1, 2p13.3-q12.1, and 6q23.3-q25.2-in a sample of 2,727 African Americans. We used logistic regression fit by generalized estimating equations and the MIX score statistic to determine which variants within ancestry-associated regions were associated with risk and responsible for the admixture signal. Fine mapping was performed by imputation, based on a previous genome-wide association study; significant variants were validated by direct genotyping. Within the 6p24.3-p12.1 locus, the most significant ancestry-adjusted SNP was rs74318745 (p = 9.4*10-11), an intronic SNP within the HLA-DRA gene that did not solely explain the admixture signal, indicating the presence of more than a single risk variant within this well-established sarcoidosis risk region. The locus on chromosome 17p13.3-13.1 revealed a novel sarcoidosis risk SNP, rs6502976 (p = 9.5*10-6), within intron 5 of the gene X-linked Inhibitor of Apoptosis Associated Factor 1 (XAF1) that accounted for the majority of the admixture linkage signal. Immunohistochemical expression studies demonstrated lack of expression of XAF1 and a corresponding high level of expression of its downstream target, X-linked Inhibitor of Apoptosis (XIAP) in sarcoidosis granulomas. In conclusion, ancestry and association fine mapping revealed a novel sarcoidosis susceptibility gene, XAF1, which has not been identified by previous genome-wide association studies. Based on the known biology of the XIAP/XAF1 apoptosis pathway and the differential expression patterns of XAF1 and XIAP in sarcoidosis granulomas, we suggest that this pathway may play a role in the maintenance of sarcoidosis granulomas.

Background: Clinicians have long regarded firm enlarged axillary nodes as suspicious for metastasis, and this has been confirmed to represent increased pressure in sentinel lymph nodes (SLN) in vivo in breast cancer. We hypothesized that measuring intranodal pressure (INP) in the operating room would correlate with metastasis size and be more sensitive than clinical observation., Methods: Intranodal pressure mmHg was measured in SLNs #1 and #2 (N = 134 and 32) in 122 patients with T1/2 cN0 and 6 controls (T0) (8 bilateral). Clinical "Level of Suspicion" (LOS) was: 0 = benign; 1 = slightly suspicious; 2 = obvious metastasis. Statistical analysis was performed to compare INP, LOS, and SLN metastasis size mm., Results: Sentinel lymph nodes met size correlated with INP (r = 0.65; p < 0.001). INP was 22.0 ± 1.3 mmHg in 35 SLNs with metastases compared with 9.3 ± 0.7 mmHg in 132 without (p < 0.001). Six groups created by combining LOS 0, 1, and 2 with INP >17 or ≤17 mmHg showed a significant (p < 0.001) correlation with SLN histology; sensitivity and specificity for LOS = 2/INP >17 mmHg = 100 % at predicting metastases; LOS = 0/INP ≤17 mmHg most often correct at predicting negative nodes (sensitivity 50 %, specificity 92.9 %, positive predictive value 55 %, negative predictive value 90.7 %). INP was better than LOS at predicting positive nodes in eight patients where INP was >17 mmHg. INP and LOS correlated significantly (p < 0.001)., Conclusions: Clinical suspicion of metastasis correlated well with INP particularly at predicting macrometastases. INP was slightly better at predicting micrometastases. Measurement of INP may be valuable adjunct when performing SLN biopsy when further axillary surgery is contemplated.

Mucinous mammary carcinoma (MC) is a tumor type with relatively favorable prognosis. Unlike the circumstances surrounding conventional invasive duct carcinoma, data are limited regarding precursor lesions for MC. This study characterizes patterns of mucinous ductal carcinoma in situ (DCIS) as a precursor lesion for MC. All slides from 130 cases of MC encountered between 2000 and 2011 at Henry Ford Hospital, Detroit, MI were reviewed to subclassify MC, identify DCIS, and explore transition patterns from DCIS to MC. Calponin, p63, chromogranin, synaptophysin, CD56, and MIB-1 immunostaining analyses were performed in 65 cases. Among 106 cases of pure (71 type A, 35 type B) and 24 cases of mixed MC, DCIS appeared in 88 (68%) specimens, with all but 4 showing luminal mucin accumulation. Dominant patterns of mucinous DCIS were cribriform/solid (66), cribriform and papillary (7), papillary (5), micropapillary (3), and flat (3). Fifty-seven (68%) cases of mucinous DCIS demonstrated transitions from DCIS to MC. Luminal mucinous distention, focal flattening and attenuation of the epithelium, and disruption of the duct wall resulting in a mucocele-like extravasation of malignant epithelia with escaping mucin was a transition pattern seen with all architectures of DCIS and in all types of MC. This was the only pattern of transition to type A MC. The epithelial outpouching, formation of a cleft with accumulation of mucin around the epithelium, and transition into mucin pools with floating tumor cell clusters was the second transition pattern that went from cribriform/solid DCIS to type B and mixed MC. DCIS preceding aggressive phenotypes of MC (type B and mixed) more often had a cribriform/solid architecture, higher nuclear grade, and higher Ki-67-labeling index (all P<0.05). In summary, mucinous DCIS is a precursor to MC with distinctive features that link patterns of DCIS with aggressive MC phenotypes. The 2 observed transitions between mucinous DCIS and MC suggest that pathogenesis of different types of MC is different correlating with less or more aggressive behavior of the latter.

Context: Breast cancer treatment has greatly evolved from radical mastectomy to more cosmetically acceptable and less-debilitating surgeries. Nipple-sparing mastectomy is increasingly done for both cancer treatment and risk reduction. The frequency of terminal duct lobular units (TDLUs) and occult neoplastic epithelial proliferation in grossly/clinically unremarkable nipples (GUNs) is not well investigated., Objective: To describe frequency of TDLUs and occult and overt neoplastic nipple involvement., Design: Nipples from 105 consecutive specimens (90 therapeutic, 15 prophylactic) were studied. Sixty-five nipples were entirely submitted to evaluate frequency of TDLUs; the rest had 1 vertical section submitted., Results: Terminal duct lobular unit was seen in 17 GUNs (26%). Six had TDLU in the base, 6 had it in the papilla, and 5 in both. Four GUNs showed lobular carcinoma in situ (1), Paget disease (1), and pagetoid extension of underlying malignancy (2). Grossly/clinically abnormal nipples had Paget disease (2), lymphovascular invasion (2), invasive carcinoma (4), and pagetoid extension (5). Involved nipples were closer to tumor (mean, 1.1 versus 3.2 cm, P < .001), had larger underlying tumors (mean, 4.3 versus 2.6 cm, P = .03) and of higher grade (P = .04), and more often had lymph node metastases (91% versus 44%, P = .007). No pathologic abnormalities were found in prophylactic mastectomy nipples., Conclusions: Terminal duct lobular units were seen in 26% of nipples. They were frequently seen in the nipple papilla. Occult neoplastic epithelial proliferation was seen in 5% of grossly/clinically unremarkable therapeutic mastectomy nipples. Pagetoid extension was the dominant spread of underlying malignancy. Overall, the nipple was more often involved by larger and higher-grade tumors located closer to the nipple. All prophylactic mastectomies had unremarkable nipples. These findings should be considered while selecting patients for nipple-sparing mastectomy.

Objective: To establish evidence-based recommendations for the molecular analysis of lung cancers that are required to guide EGFR- and ALK-directed therapies, addressing which patients and samples should be tested, and when and how testing should be performed., Participants: Three cochairs without conflicts of interest were selected, one from each of the 3 sponsoring professional societies: College of American Pathologists, International Association for the Study of Lung Cancer, and Association for Molecular Pathology. Writing and advisory panels were constituted from additional experts from these societies., Evidence: Three unbiased literature searches of electronic databases were performed to capture published articles from January 2004 through February 2012, yielding 1533 articles whose abstracts were screened to identify 521 pertinent articles that were then reviewed in detail for their relevance to the recommendations. EVIDENCE was formally graded for each recommendation., Consensus Process: Initial recommendations were formulated by the cochairs and panel members at a public meeting. Each guideline section was assigned to at least 2 panelists. Drafts were circulated to the writing panel (version 1), advisory panel (version 2), and the public (version 3) before submission (version 4)., Conclusions: The 37 guideline items address 14 subjects, including 15 recommendations (evidence grade A/B). The major recommendations are to use testing for EGFR mutations and ALK fusions to guide patient selection for therapy with an epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) inhibitor, respectively, in all patients with advanced-stage adenocarcinoma, regardless of sex, race, smoking history, or other clinical risk factors, and to prioritize EGFR and ALK testing over other molecular predictive tests. As scientific discoveries and clinical practice outpace the completion of randomized clinical trials, evidence-based guidelines developed by expert practitioners are vital for communicating emerging clinical standards. Already, new treatments targeting genetic alterations in other, less common driver oncogenes are being evaluated in lung cancer, and testing for these may be addressed in future versions of these guidelines., (Copyright © 2013 College of American Pathologists, American Society for Investigative Pathology, Association for Molecular Pathology, and the International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: Gene promoter hypermethylation may be useful as a biomarker for cancer risk in histopathologically benign prostate specimens., Materials and Methods: We performed a nested case-control study of gene promoter methylation status for 5 genes (APC, RARB, CCND2, RASSF1 and MGMT) measured in benign biopsy specimens from 511 prostate cancer case-control pairs. We estimated the overall and race stratified risk of subsequent prostate cancer associated with methylation status., Results: On race stratified analysis RARB methylation was associated with a higher cancer risk in black American men (OR 2.18, 95% CI 1.39-3.44). APC methylation was associated with an increased risk of high grade tumors (OR 2.43, 95% CI 1.20-4.90), which was higher in black than in white men (OR 3.21 vs 2.04). In cases RARB and APC gene methylation in benign prostate samples persisted in matched malignant specimens. In black cases the combined risk associated with RARB and APC methylation (OR 3.04, 95% CI 1.44-6.42) was greater than the individual risk of each gene and significantly different from that in white cases (OR 1.14, 95% CI 0.56-2.30)., Conclusions: RARB gene methylation in histopathologically benign prostate samples was associated with a statistically significant increased risk of subsequent prostate cancer in black men. Methylation data on additional genes may improve risk stratification and clinical decision making algorithms for cancer screening and diagnosis., (Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Aurora-A is a mitotic kinase implicated in oncogenesis and is known to be overexpressed in B-cell lymphomas and plasma cell myeloma. The expression of Aurora-A kinase (henceforth referred to as Aurora-A) in T-cell lymphomas is not well characterized. In this study, we assessed Aurora-A expression by immunohistochemical analysis in 100 lymphomas encompassing a variety of T-cell lymphomas as categorized in the World Health Organization classification. Aurora-A expression was highest in anaplastic large-cell lymphomas and variably expressed in other types of T-cell lymphomas. In addition, the pattern of Aurora-A expression was predominantly cytoplasmic in ALK-positive anaplastic large-cell lymphoma and was nuclear in ALK-negative anaplastic large-cell lymphoma and other T-cell lymphomas, suggesting altered biochemical mechanisms of Aurora-A nuclear transport in ALK-positive anaplastic large-cell lymphoma. Reverse transcriptase-PCR analysis showed that Aurora-A is more highly expressed in ALK-positive anaplastic large-cell lymphoma than in ALK-negative anaplastic large-cell lymphoma, and is relatively lower in peripheral T-cell lymphomas. Using western blot analysis and the DEL cell line (derived from ALK-positive anaplastic large-cell lymphoma), we showed that Aurora-A expression is decreased after treatment with either MYC or MEK inhibitors, consistent with the MYC and MAP kinase signaling pathways being involved in driving Aurora-A expression; the greatest decrease was observed after MYC inhibition. These findings provide insights into the possible importance of Aurora-A overexpression in anaplastic large-cell lymphoma pathogenesis, and also suggest that Aurora-A inhibition could be a potential therapeutic approach for patients with anaplastic large-cell lymphoma., Competing Interests: Disclosure/conflict of interest The authors declare no conflict of interest.

Benign changes ranging from atrophy and inflammation to high-grade prostatic intraepithelial neoplasia (HGPIN) are common findings on prostate core needle biopsies. Although atrophy and inflammation may be precursors of prostate cancer, only HGPIN is currently recommended to be included in surgical pathology reports. To determine whether these benign findings increase prostate cancer risk, we conducted a case-control study nested within a historical cohort of 6692 men with a benign prostate specimen collected between 1990 and 2002. The analytic sample included 574 case-control pairs comprised of cases diagnosed with prostate cancer a minimum of 1 year after cohort entry and controls matched to cases on date and age at cohort entry, race, and type of specimen. The initial benign specimen was reviewed for presence of HGPIN, atrophy (simple, lobular, and partial) and inflammation (glandular and/or stromal). HGPIN significantly increased risk for prostate cancer (odds ratio (OR)=2.00; 95% confidence interval (CI)=1.25-3.20). Inflammation within the stromal compartment was associated with decreased risk (OR=0.66; CI=0.52-0.84), and diffuse stromal inflammation of severe grade had the strongest inverse association with risk (OR=0.21; CI=0.07-0.62). In a model adjusted for prostate-specific antigen (PSA) level at cohort entry and inflammation, simple atrophy was associated with a 33% increased prostate cancer risk that was marginally significant (P=0.03). Clinicians should consider patterns and extent of inflammation when managing high-risk patients with negative biopsy results. Identifying benign inflammatory processes that underlie high PSA levels would help to reduce the number of unnecessary repeated prostate biopsies.

Background: Mutations in the KRAS gene are associated with poor response to epidermal growth factor receptor inhibitors used in the treatment of metastatic colorectal cancer. Factors influencing KRAS test results in tumor specimens include: tumor heterogeneity, sample handling, slide preparation, techniques for tumor enrichment, DNA preparation, assay design and sensitivity. We evaluated comparability and consistency of KRAS test results among five laboratories currently being used to determine KRAS mutation status of metastatic colorectal cancer specimens in a large, multi-center observational study., Findings: Twenty formalin-fixed paraffin-embedded human colorectal cancer samples from colon resections previously tested for KRAS mutations were selected based on mutation status (6 wild type, 8 codon 12 mutations, and 6 codon 13 mutations). We found good agreement across laboratories despite differences in mutation detection methods. Eighteen of twenty samples (90%) were concordant across all five labs. Discordant results are likely not due to laboratory error, but instead to tumor heterogeneity, contamination of the tumor sample with normal tissue, or analytic factors affecting assay sensitivity., Conclusions: Our results indicate commercial and academic laboratories provide reliable results for the common KRAS gene mutations at codons 12 and 13 when an adequate percentage of tumor cells is present in the sample.

The authors analyzed 52 cases of female breast angiolipoma (AL). Age distribution was 25 to 80 years of age (56.81 ± 12.78). Most cases showed vascularity below 50%, and 14 cases had vascularity >50%. Cellular and low-vascularity ALs had different clinical and radiological presentations. The mean size was 7.00 ± 3.62 mm for cellular ALs and 19.61 ± 7.58 mm for low-vascularity ALs. In any paucicellular area, the authors could identify a cluster of at least 3 interconnected vessels. The endothelium was mostly flat with uniform, hyperchromatic nuclei, and mitoses and nucleoli were absent. Fibrin thrombi in proliferating capillaries were noted in 96% of cases. Low-vascularity AL can be reliably distinguished on needle core biopsy from other lipomatous and vascular tumors of the breast. Tortuosity and proliferation of capillaries with at least 3 interconnected capillary channels in 1 focus with associated fibrin thrombi constitute a very strong clue for the diagnosis of AL on a breast needle core biopsy. Definite diagnosis of cellular AL is not always feasible because of rare cases with mitotic activity and cellular atypia. Excision is often recommended for cellular AL.

Patients with poorly differentiated thyroid cancers (PDTC), anaplastic thyroid cancers (ATC), and radioactive iodine-refractory (RAIR) differentiated thyroid cancers have a high mortality, particularly if positive on [(18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET). To obtain comprehensive genetic information on advanced thyroid cancers, we designed an assay panel for mass spectrometry genotyping encompassing the most significant oncogenes in this disease: 111 mutations in RET, BRAF, NRAS, HRAS, KRAS, PIK3CA, AKT1, and other related genes were surveyed in 31 cell lines, 52 primary tumors (34 PDTC and 18 ATC), and 55 RAIR, FDG-PET-positive recurrences and metastases (nodal and distant) from 42 patients. RAS mutations were more prevalent than BRAF (44 versus 12%; P = 0.002) in primary PDTC, whereas BRAF was more common than RAS (39 versus 13%; P = 0.04) in PET-positive metastatic PDTC. BRAF mutations were highly prevalent in ATC (44%) and in metastatic tumors from RAIR PTC patients (95%). Among patients with multiple metastases, 9 of 10 showed between-sample concordance for BRAF or RAS mutations. By contrast, 5 of 6 patients were discordant for mutations of PIK3CA or AKT1. AKT1&#95;G49A was found in 9 specimens, exclusively in metastases. This is the first documentation of AKT1 mutation in thyroid cancer. Thus, RAIR, FDG-PET-positive metastases are enriched for BRAF mutations. If BRAF is mutated in the primary, it is likely that the metastases will harbor the defect. By contrast, absence of PIK3CA/AKT1 mutations in one specimen may not reflect the status at other sites because these mutations arise during progression, an important consideration for therapies directed at phosphoinositide 3-kinase effectors.

Purpose: KRAS mutations are found in approximately 25% of lung adenocarcinomas in Western countries and, as a group, have been strongly associated with cigarette smoking. These mutations are predictive of poor prognosis in resected disease as well as resistance to treatment with erlotinib or gefitinib., Experimental Design: We determined the frequency and type of KRAS codon 12 and 13 mutations and characterized their association with cigarette smoking history in patients with lung adenocarcinomas., Results: KRAS mutational analysis was done on 482 lung adenocarcinomas, 81 (17%) of which were obtained from patients who had never smoked cigarettes. KRAS mutations were found in 15% (12 of 81; 95% confidence intervals, 8-24%) of tumors from never smokers. Similarly, 22% (69 of 316; 95% confidence intervals, 17-27%) of tumors from former smokers, and 25% (21 of 85; 95% confidence intervals, 16-35%) of tumors from current smokers had KRAS mutations. The frequency of KRAS mutation was not associated with age, gender, or smoking history. The number of pack years of cigarette smoking did not predict an increased likelihood of KRAS mutations. Never smokers were significantly more likely than former or current smokers to have a transition mutation (G-->A) rather than the transversion mutations known to be smoking-related (G-->T or G-->C; P < 0.0001)., Conclusions: Based on our data, KRAS mutations are not rare among never smokers with lung adenocarcinoma and such patients have a distinct KRAS mutation profile. The etiologic and biological heterogeneity of KRAS mutant lung adenocarcinomas is worthy of further study.

Cancer-testis (CT) antigens are expressed in a variety of malignant tumors, but in normal adult tissue, they are only expressed in testicular germ cells. Owing to this tumor-associated expression pattern, these antigens are of major interest as potential targets for immunotherapy and possibly for diagnostic purposes. This study was performed to analyze the expression of four CT antigens, NY-ESO-1, MAGE-A3, MAGE-A4, and CT7/MAGE-C1, in endometrial carcinoma using immunohistochemistry, and to correlate expression with histologic subtypes, grade, and expression of WT1 and p53. Formalin-fixed paraffin-embedded tissues of 130 endometrial carcinomas of the following types and grades were analyzed using a tissue microarray: 85 endometrioid carcinomas (FIGO grade 1, 39; grade 2, 11; and grade 3, 35), 18 papillary serous carcinomas, 12 clear cell carcinomas, 13 malignant mixed mullerian tumors, one mucinous adenocarcinoma, and one undifferentiated carcinoma. The following anti-CT monoclonal antibodies/antigens were studied by immunohistochemistry: monoclonal antibody ES121/NY-ESO-1, monoclonal antibody M3H67/MAGE-A3, monoclonal antibody 57B/MAGE-A4, and monoclonal antibody CT7-33/CT7. The CT expression data were compared to WT1 and p53 protein expression as analyzed in a previous study. Positive staining with anti-CT monoclonal antibodies was graded as follows: focal, <5% positive cells; 1+, 5-25% cells; 2+, 26-50% cells; 3+, 51-75%; and 4+, >75% cells. The 3+ and 4+ staining patterns were considered homogeneous patterns of potential clinical significance and were scored positive for statistical analysis. In low-grade tumors, the most immunoreactivity was seen with mAb M3H67 but little labeling was observed with the other monoclonal antibodies. In high-grade tumors, monoclonal antibodies M3H67 (25%), 57B (23%), and CT7-33 (20%) showed the highest reactivity, while ES121 showed the lowest immunoreactivity (6%). The staining pattern was mostly heterogeneous. Statistical significance was found solely for the correlation of monoclonal antibody 57B staining and p53 expression. No correlation was found for any anti-CT monoclonal antibody staining and clinical stage or for anti-CT staining and WT1 expression. CT antigens CT7, MAGE-A3 and MAGE-A4, but not NY-ESO-1, are expressed in high-grade endometrial carcinomas, and expression of MAGE-A4 is correlated with the presence of overexpressed p53.

Systemic AL amyloidosis (AL) is a disorder in which light chains form fibrillar deposits, leading to organ dysfunction and death. Rarely, AL has been associated with non-Hodgkin's lymphoma (NHL), although this association has not been well characterized. We report a series of six patients with AL associated with NHL, primarily lymphoplasmacytic lymphoma. Organ involvement was variable, with frequent bulky lymphadenopathy and visceral cavity deposits, but no cardiac involvement. Positron emission tomography scans were negative. Bone marrow and lymph node biopsies showed a mixed population of CD20+ lymphoid and CD138+ plasma cells. Serum free light chains were elevated, and correlated with response to therapy. Immunoglobulin light chain variable region (Ig VL) germline gene use was typical for AL, reflecting previously observed correlations between germline gene use and organ tropism. Five patients received rituximab-based therapies with two responses. Two patients underwent autologous stem cell transplantation with one complete haematological response. Four patients survive at 10-132 months from diagnosis. AL with NHL has distinctive clinical features but employs the same Ig VL gene repertoire as AL with clonal plasma cell dyscrasias. Serial serum free light chain levels are useful for tracking response to therapy. Treatments aimed at both lymphoid and plasma cell components appear warranted.

Abnormal cilia were demonstrated in the lining epithelial cells of three cases of intraspinal endodermal (bronchogenic) cyst. The changes comprised a wide spectrum of ultrastructural abnormalities, including (a). cilia with abnormal axonemal microtubules, (b). swollen cilia, (c). compound cilia with or without excessive ciliary matrix, (d). naked cilia without limiting membrane, and (e). intracytoplasmic cilia and aggregates of microtubules. Of these, compound cilia and swollen cilia were most common. Cilia with dynein arm deficiency were not observed. Ciliary abnormalities found in the present study were very similar to those described in the bronchial epithelium of various diseases. The present findings suggest that the lining epithelium of intraspinal endodermal cyst shares similar ciliogenesis and susceptibility to abnormal ciliary formation as that of the bronchial epithelium.

Background: Metastasis of histologically benign chondroblastoma is a rare event. The authors report a new case, 12th in the literature, wherein multiple lung metastases appeared almost simultaneously with the primary lesion in the right talus bone., Methods: A histologic evaluation of the primary lesion in the talus and the pulmonary metastasis was performed, and an ultrastructural study of the latter was done. Published literature on metastasizing chondroblastoma was reviewed to identify any consistency in the pattern and the outcome., Results: Metastasis of chondroblastoma is uncommon but well known. Although radiologic and histologic aggressive features have been sought, they do not necessarily correlate with the outcome., Conclusions: Metastasis in chondroblastoma has been insufficiently stressed in the literature, unlike metastasis in giant cell tumors. The purpose of this case report is not only to document this uncommon event (the 12th case of lung metastasis) but also to emphasize that patients with chondroblastoma may have metastasis at presentation. Hence, all patients need to be evaluated regularly from the onset for possible lung metastasis so that deposits can be detected early for total resection.