[Incidentally discovered ectopic tissue in the central neck region (level VI) of the neck - A case series, retrospective analysis and literature review]. / Incidentálisan felfedezett ektópiás szövetmaradványok elofordulása a nyaki VI. (centrális) régióban ­ Esetsorozat ismertetése, retrospektív feldolgozás és irodalmi áttekintés.

The thymus derives from the third branchial pouch, which migrates to the mediastinum through the central region of the neck. During the migration, particles split off and develop separately. The prevalence of ectopic thymus is 20-40%. The purpose of this retrospective case series study was to investigate the prevalence of embryological tissue remnants in the central region, in patients treated for thyroid lesions. Between January 1 2018 and September 1 2020, 84 patients who underwent central neck dissection were selected. Clinicopathological data as age, gender, histopathological result and TNM stage were analyzed. Ectopic tissue in the central neck region was discovered in 28 cases. The prevalence of ectopic lesions showed increase in Stage I thyroid carcinomas. There was no significant correlation with patients' age, gender, or with the stage. We emphasize the clinicopathological role of ectopic tissues, which can occur in the central region of the neck.

Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials.

The SOFT and TEXT randomized phase III trials investigated adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) early breast cancer. We investigated the prognostic and predictive value of centrally assessed levels of estrogen receptor (ER), progesterone receptor (PgR), and Ki-67 expression in women with HER2-negative disease. Of 5707 women enrolled, 4115 with HER2-negative (HR+/HER2-) disease had ER, PgR, and Ki-67 centrally assessed by immunohistochemistry. Breast cancer-free interval (BCFI) was defined from randomization to first invasive local, regional, or distant recurrence or contralateral breast cancer. The prognostic and predictive values of ER, PgR and Ki-67 expression levels were assessed using Cox modeling and STEPP methodology. In this HR+/HER2- population, the median ER, PgR, and Ki-67 expressions were 95, 90, and 18 % immunostained cells. As most patients had strongly ER-positive tumors, the predictive value of ER levels could not be investigated. Lower PgR and higher Ki-67 expression were associated with reduced BCFI. There was no consistent evidence of heterogeneity of the relative treatment effects according to PgR or Ki-67 expression levels, though there was a greater 5-year absolute benefit of exemestane + ovarian function suppression (OFS) versus tamoxifen with or without OFS at lower levels of PgR and higher levels of Ki-67. Women with poor prognostic features of low PgR and/or high Ki-67 have greater absolute benefit from exemestane + OFS versus tamoxifen + OFS or tamoxifen alone, but individually PgR and Ki-67 are of limited predictive value for selecting adjuvant endocrine therapy for premenopausal women with HR+/HER2- early breast cancer.

[Quality assurance of rapid on-site evaluation of CT-guided fine-needle aspiration cytology of lung nodules]. / A CT-vezérelt vékonytu-aspirációs citológiai vizsgálat minoségbiztosítása a tüdodaganatok diagnosztikájában.

INTRODUCTION: The methods available for the diagnosis of lung cancer include radiologic, cytologic and pathologic procedures. AIMS: The aim of this study was to determine the quality assurance of CT guided fine needle aspiration cytology of lung nodules. METHODS: Cytology results were rated to 4 categories (positive; suspicious; negative; not representative). All cytology reports were compared with the final histology diagnosis. RESULTS: A total of 128 patients underwent CT-guided percutaneous fine-needle aspiration biopsy cytology (63 males; 65 females; mean age 62.8 years). Smears were adequate in 99 cases and inadequate in 29 cases. The average diameter of the nodules was 3.28 cm. Thirty three (25.6%) of the cases were histologically verified and 2 falsely negative and 2 falsely positive cases were detected. The sensitivity and the positive predictive value were 88.8% and 88.8%, respectively. Pneumothorax developed in 7 (5.4%) cases. CONCLUSION: These results suggest that CT-guided transthoracic fine needle aspiration cytology has a high diagnostic accuracy and an acceptable complication rate. The auditing valves of the results meet the proposed threshold values.

[Modern pathologic diagnostics in breast cancer]. / Az emlorák korszeru patológiai diagnosztikája.

The diagnosis of breast cancer is morphologically based. Pathologic parameters, such as tumor size, lymph node status, and histological grade are well accepted to guide treatment decisions in clinical practice. Estrogen receptor, progesterone receptor and HER2 status are also routinely assessed in today's pathology laboratories to provide further information on predictive and prognostic factors affecting patients' care. Newer molecular techniques, including gene-expression profiling have been widely used to study breast cancer and several molecular prognostic tests already available for clinical use stemmed from these scientific efforts. Authors review prognostically important aspects of the diagnostic pathology and the molecular classification of invasive breast cancer.

[Correlation between microsatellite instability and morphology in colorectal cancer]. / A microsatellita-státus és a morfológiai kép összefüggése vastagbélrákokban.

Microsatellite instability (MSI) influences the development and clinical course of colorectal cancers (CRCs) and induce specific morphological alterations of such neoplasms, therefore hematoxylin-eosin (H&E) based histology allows to predict the microsatellite status of a given tumor. The aim of this article is to demonstrate clinicopathological features that are useful in recognition of microsatellite-stable and -unstable CRCs on routine histological examination. In the Center of Surgical and Molecular Pathology of National Institute of Oncology, from 384 CRC cases 26 hereditary non-polyposis colorectal cancers (HNPCC), 22 sporadic high-level microsatellite-instable (MSI-H) cancers and 76 microsatellite-stable (MSS) or low-level MSI (MSI-L) CRCs were selected on the basis of the localization, clinical stage, microsatellite status, and patient age at the time of the diagnosis. Our results showed that we can recognize MSS/MSI-L carcinomas, HNPCCs and sporadic MSI-H tumors with high probability on the base of clinicopathological features like patient's age, tumor localization, clinical stage and histological characteristics of CRCs, even if the genetic MSI test is not available. The main morphological characteristics related to microsatellite instability are intratumoral or stromal infiltrating lymphocytes/leukocytes, large, vesicular nuclei with prominent nucleoli, and expansive infiltrative edge of the tumors. Careful and detailed morphological analysis of colorectal cancers helps to select the appropriate molecular method to determine the molecular features that influence the clinical care of patients and allow to consider the most appropriate anti-tumor therapy.

Identification of DOK genes as lung tumor suppressors.

Genome-wide analyses of human lung adenocarcinoma have identified regions of consistent copy-number gain or loss, but in many cases the oncogenes and tumor suppressors presumed to reside in these loci remain to be determined. Here we identify the downstream of tyrosine kinase (Dok) family members Dok1, Dok2 and Dok3 as lung tumor suppressors. Single, double or triple compound loss of these genes in mice results in lung cancer, with penetrance and latency dependent on the number of lost Dok alleles. Cancer development is preceded by an aberrant expansion and signaling profile of alveolar type II cells and bronchioalveolar stem cells. In human lung adenocarcinoma, we identify DOK2 as a target of copy-number loss and mRNA downregulation and find that DOK2 suppresses lung cancer cell proliferation in vitro and in vivo. Given the genomic localization of DOK2, we propose it as an 8p21.3 haploinsufficient human lung tumor suppressor.

Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.

Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.

Lung adenocarcinoma: modification of the 2004 WHO mixed subtype to include the major histologic subtype suggests correlations between papillary and micropapillary adenocarcinoma subtypes, EGFR mutations and gene expression analysis.

The histologic heterogeneity of lung adenocarcinoma creates a variety of complex challenges to pathologists in analyzing the various subtypes. Current classification schemas do not take into account the major subtype. We analyzed 100 cases for clinical, pathologic, and molecular features using a modification of the 2004 World Health Organization (WHO) classification to record the major component in the mixed subtype tumors. The tumors were analyzed for KRAS mutation and epidermal growth factor receptor (EGFR) by mutation, chromogenic in situ hybridization, and immunohistochemistry for EGFR and phosphorylated EGFR. Gene expression analysis was performed using HG-U133A Affymetrix oligonucleotide microarrays revealing 3 gene clusters. The most common major histologic subtype was papillary (37%) followed by acinar (30%), solid (25%) and bronchioloalveolar (7%) carcinoma (BAC), although no pure BACs were seen. Sixteen tumors harbored EGFR mutations and 14 KRAS mutations. Papillary adenocarcinoma strongly correlated with EGFR mutation (P<0.001) and gene profile Cluster 1 (P=0.006) with weaker correlations with low grade (P=0.038) and favorable behavior in Stage 1 patients (P=0.047). Micropapillary subtype correlated strongly with EGFR mutation (P<0.001) and weakly with Cluster 1 (P=0.030). Solid adenocarcinoma strongly correlated with gene profile Cluster 3 (P=0.001) and worse survival (P=0.001). BAC as a major component strongly correlated with gene Cluster 2 (P=0.001). Cluster 1 correlated strongly with less smoking (P<0.001), papillary histology (P<0.001), and EGFR mutations (P<0.001). Cluster 3 strongly correlated with heavier smoking (P<0.001), larger tumor size (P<0.001), solid subtype (P<0.001), and poor grade (P=0.004); weak correlations were found with KRAS mutation (P=0.025). No correlation was found with BAC and EGFR by mutation, chromogenic in situ hybridization or immunohistochemistry. Higher stage (P<0.001), grade (P<0.001), and solid subtype (P=0.001) correlated with shorter survival. Our data suggest that EGFR mutations are associated with papillary adenocarcinoma and gene profile Cluster 1. We discovered this only because we used a comprehensive approach examining in detail all histologic subtypes and we modified the 2004 WHO mixed subtype to include the major histologic subtype. As we do not know the major genetic pathways of 30% to 70% of lung adenocarcinomas, the comprehensive histologic subtyping we propose gives advantage for recognition of unanticipated histologic-genetic correlations that might not be detected using classification systems that focus primarily on specific aspects of adenocarcinomas such as BAC or EGFR mutations. Such an approach should be considered in future studies for validation in other datasets.

MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.

In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR(T790M) mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR(T790M) mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.

A gene expression signature predicts survival of patients with stage I non-small cell lung cancer.

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States. Nearly 50% of patients with stages I and II non-small cell lung cancer (NSCLC) will die from recurrent disease despite surgical resection. No reliable clinical or molecular predictors are currently available for identifying those at high risk for developing recurrent disease. As a consequence, it is not possible to select those high-risk patients for more aggressive therapies and assign less aggressive treatments to patients at low risk for recurrence. METHODS AND FINDINGS: In this study, we applied a meta-analysis of datasets from seven different microarray studies on NSCLC for differentially expressed genes related to survival time (under 2 y and over 5 y). A consensus set of 4,905 genes from these studies was selected, and systematic bias adjustment in the datasets was performed by distance-weighted discrimination (DWD). We identified a gene expression signature consisting of 64 genes that is highly predictive of which stage I lung cancer patients may benefit from more aggressive therapy. Kaplan-Meier analysis of the overall survival of stage I NSCLC patients with the 64-gene expression signature demonstrated that the high- and low-risk groups are significantly different in their overall survival. Of the 64 genes, 11 are related to cancer metastasis (APC, CDH8, IL8RB, LY6D, PCDHGA12, DSP, NID, ENPP2, CCR2, CASP8, and CASP10) and eight are involved in apoptosis (CASP8, CASP10, PIK3R1, BCL2, SON, INHA, PSEN1, and BIK). CONCLUSIONS: Our results indicate that gene expression signatures from several datasets can be reconciled. The resulting signature is useful in predicting survival of stage I NSCLC and might be useful in informing treatment decisions.

Recurrent giant fibroepithelial stromal polyp of the vulva associated with congenital lymphedema.

BACKGROUND: The relatively site-specific mesenchymal lesions of the vulvovaginal region can exhibit superficially overlapping histological features and can be diagnostically challenging. Fibroepithelial stromal polyp is generally an easily recognizable entity, but certain cases cause differential diagnostic problems. CASE: We present a case of a 16-year-old girl with a 10-cm polypoid lesion localized to the left labium. The patient has therapy resistant congenital lymphedema localized to the left arm and leg. The labial lesion was resected and recurred after 12 months and 6 years following the initial treatment. Histologically, it exhibited characteristics of a fibroepithelial stromal polyp with scattered bizarre multinucleated giant cells and ectatic tortuous lymphatic spaces. CONCLUSION: This vulvar lesion represents a unique example of giant fibroepithelial stromal polyp developed in association with Nonne-Milroy-Meiges syndrome.