BRCA1 and BRCA2 carriers with breast, ovarian and prostate cancer demonstrate a different pattern of metastatic disease compared with non-carriers: results from a rapid autopsy programme.

Aim: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non-carriers with breast, ovarian and prostate cancer from a rapid autopsy programme.

Methods And Results: The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants' pattern of disease for the different cancers and mutation subgroups.

Development of a Multi-Institutional Prediction Model for Three-Year Survival Status in Patients with Uterine Leiomyosarcoma (AGOG11-022/QCGC1302 Study).

Background: The existing staging systems of uterine leiomyosarcoma (uLMS) cannot classify the patients into four non-overlapping prognostic groups. This study aimed to develop a prediction model to predict the three-year survival status of uLMS.

Methods: In total, 201 patients with uLMS who had been treated between June 1993 and January 2014, were analyzed.

Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

Purpose: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA.

Patients And Methods: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL.

Pitfalls and controversies in pathology impacting breast cancer management.

: Breast cancer is a heterogeneous disease, at morphological, molecular, and clinical levels and this has significant implications for the diagnosis and management of the disease. The introduction of breast screening, and the use of small tissue sampling for diagnosis, the recognition of new morphological and molecular subtypes, and the increasing use of neoadjuvant therapies have created challenges in pathological diagnosis and classification.: Areas of potential difficulty include columnar cell lesions, particularly flat epithelial atypia, atypical ductal hyperplasia, lobular neoplasia and its variants, and a range of papillary lesions.

Breast cancer metastasis to gynaecological organs: a clinico-pathological and molecular profiling study.

Breast cancer metastasis to gynaecological organs is an understudied pattern of tumour spread. We explored clinico-pathological and molecular features of these metastases to better understand whether this pattern of dissemination is organotropic or a consequence of wider metastatic dissemination. Primary and metastatic tumours from 54 breast cancer patients with gynaecological metastases were analysed using immunohistochemistry, DNA copy-number profiling, and targeted sequencing of 386 cancer-related genes.

Mixed ductal-lobular carcinomas: evidence for progression from ductal to lobular morphology.

Mixed ductal-lobular carcinomas (MDLs) show both ductal and lobular morphology, and constitute an archetypal example of intratumoural morphological heterogeneity. The mechanisms underlying the coexistence of these different morphological entities are poorly understood, although theories include that these components either represent 'collision' of independent tumours or evolve from a common ancestor. We performed comprehensive clinicopathological analysis of a cohort of 82 MDLs, and found that: (1) MDLs more frequently coexist with ductal carcinoma in situ (DCIS) than with lobular carcinoma in situ (LCIS); (2) the E-cadherin-catenin complex was normal in the ductal component in 77.

Looking beyond human papillomavirus (HPV) genotype 16 and 18: Defining HPV genotype distribution in cervical cancers in Australia prior to vaccination.

Australia has implemented a high-coverage HPV vaccination program but has not, to date, established the distribution of HPV types that occur in cervical cancers in Australia. This information is important for determining the potential for cervical cancer prevention with both current and broader spectrum HPV vaccines. We analysed 847 cervical cancers diagnosed 2005 to 2015 in tertiary centres in the three most populous Australian states with resolution of specimens containing multiple HPV types using laser-capture microdissection.

Relationship of the Breast Ductal Carcinoma Immune Microenvironment with Clinicopathological and Genetic Features.

The immune microenvironment of breast ductal carcinoma (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown. We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number ( = 55) and mutation data ( = 20). TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%-90%).

Breast ductal carcinoma in situ carry mutational driver events representative of invasive breast cancer.

The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%).

External quality assurance in nongynecologic cytology: The Australasian experience.

Background: The Royal College of Pathologists of Australasia Cytopathology Quality Assurance Program has operated an external quality assurance program in nongynecologic cytopathology since 1993. Glass slide preparations of a wide range of nongynecologic cases were circulated to approximately 200 cytopathology laboratories in 16 countries.

Methods: General nongynecologic cytology cases were manufactured from residual specimens after routine diagnosis.

Novel highly specific anti-periostin antibodies uncover the functional importance of the fascilin 1-1 domain and highlight preferential expression of periostin in aggressive breast cancer.

Periostin (POSTN), a secreted homodimeric protein that binds integrins αvβ3, αvβ5, and α6β4, was originally found to be expressed in fetal tissues and in the adult upon injury particularly bone fractures due to its role in remodelling and repair. Recently it was found to be over-expressed in human breast cancer and a variety of other tumour types including head and neck squamous cell carcinoma, where its overexpression correlates with increased tumour invasion. Progress in studying its functional role in tumour pathogenesis has been hampered by the paucity of antibodies for its specific and sensitive detection.

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing.

Lynch syndrome and cervical cancer.

Carriers of germline mutations in DNA mismatch repair (MMR) genes are at increased risk of several cancers including colorectal and gynecologic cancers (Lynch syndrome). There is no substantial evidence that these mutations are associated with an increased risk of cervical cancer. A total of 369 families with at least one carrier of a mutation in a MMR gene (133 MLH1, 174 MSH2, 35 MSH6 and 27 PMS2) were ascertained via population cancer registries or via family cancer clinics in Australia, New Zealand, Canada, and USA.

Which are more correctly diagnosed: conventional Papanicolaou smears or Thinprep samples? A comparative study of 9 years of external quality-assurance testing.

Background: The Royal College of Pathologists of Australasia Cytopathology Quality Assurance Program offers external testing in gynecologic cytology to Australasian and international laboratories. Laboratory interpretation of conventional Papanicolaou (Pap) smears is compared with interpretation of liquid-based cervical cytologic (ThinPrep) samples.

Methods: Conventional Pap smears and ThinPrep samples were distributed to participating laboratories annually over 9 years (from 2004 to 2012), and a range of entities was tested.

A multiresidue screen for the analysis of toxicants in bovine rumen contents.

Analysis of rumen contents is helpful in solving poisoning cases when ingestion of a toxic substance by cattle or other ruminant animals is suspected. The most common technique employs extraction of the sample with organic solvent followed by clean-up method(s) before analysis with gas chromatography-mass spectrometry equipped with a library of mass spectra to help identify unknowns. A rapid method using magnesium sulfate, primary secondary amine, and C18 sorbents following principles of QuEChERS to clean up rumen contents samples is reported herein.

Molecular classification of breast cancer.

Breast cancer is a complex, multifaceted disease encompassing a great variety of entities that show considerable variation in clinical, morphological and molecular attributes. Traditional classifications including histological assessment and clinical staging are used to guide patient management. In recent years, there has been exponential progress in molecular analysis with profound implications for our understanding of breast cancer biology and, hence, classification.

Tumor mismatch repair immunohistochemistry and DNA MLH1 methylation testing of patients with endometrial cancer diagnosed at age younger than 60 years optimizes triage for population-level germline mismatch repair gene mutation testing.

Purpose: Clinicopathologic data from a population-based endometrial cancer cohort, unselected for age or family history, were analyzed to determine the optimal scheme for identification of patients with germline mismatch repair (MMR) gene mutations.

Patients And Methods: Endometrial cancers from 702 patients recruited into the Australian National Endometrial Cancer Study (ANECS) were tested for MMR protein expression using immunohistochemistry (IHC) and for MLH1 gene promoter methylation in MLH1-deficient cases. MMR mutation testing was performed on germline DNA of patients with MMR-protein deficient tumors.

Anticoagulant rodenticides in red-tailed hawks, Buteo jamaicensis, and great horned owls, Bubo virginianus, from New Jersey, USA, 2008-2010.

Liver samples from red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus) were analyzed for anticoagulant rodenticides. Residues of one or more second generation anticoagulant rodenticides (SGARs) were detected in 81 % of red-tailed hawks and 82 % of great horned owls. The most frequently detected SGAR was brodifacoum, which was detected in 76 % of red-tailed hawks and 73 % of great horned owls.

Metastatic progression of breast cancer: insights from 50 years of autopsies.

There remain no clear guidelines for the optimal management of patients with metastatic breast cancer. To better understand its natural history, we undertook a detailed examination of 197 autopsies performed on women who died of breast cancer. We reviewed clinical, treatment and pathological aspects of all cases and, additionally, pathological features and biomarker expression (ER, PgR, HER2, EGFR, p53, Ki67, c-Kit, CK AE1/AE3) were assessed in detail for the primary tumour and matched metastases for 55 of the cases.

Evaluating the repair of DNA derived from formalin-fixed paraffin-embedded tissues prior to genomic profiling by SNP-CGH analysis.

Pathology archives contain vast resources of clinical material in the form of formalin-fixed paraffin-embedded (FFPE) tissue samples. Owing to the methods of tissue fixation and storage, the integrity of DNA and RNA available from FFPE tissue is compromized, which means obtaining informative data regarding epigenetic, genomic, and expression alterations can be challenging. Here, we have investigated the utility of repairing damaged DNA derived from FFPE tumors prior to single-nucleotide polymorphism (SNP) arrays for whole-genome DNA copy number analysis.

Lynch syndrome-associated breast cancers do not overexpress chromosome 11-encoded mucins.

Mismatch repair-deficient breast cancers may be identified in Lynch syndrome mutation carriers, and have clinicopathological features in common with mismatch repair-deficient colorectal and endometrial cancers such as tumour-infiltrating lymphocytes and poor differentiation. Mismatch repair-deficient colorectal cancers frequently show mucinous differentiation associated with upregulation of chromosome 11 mucins. The aim of this study was to compare the protein expression of these mucins in mismatch repair-deficient and -proficient breast cancers.