Influence of Biopsy Technique on Molecular Genetic Tumor Characterization in Non-Small Cell Lung Cancer—The Prospective, Randomized, Single-Blinded, Multicenter PROFILER Study Protocol

The detection of molecular alterations is crucial for the individualized treatment of advanced non-small cell lung cancer (NSCLC). Missing targetable alterations may have a major impact on patient’s progression free and overall survival. Although laboratory testing for molecular alterations has continued to improve; little is known about how biopsy technique affects the detection rate of different mutations. In the retrospective study detection rate of epidermal growth factor (EGFR) mutations in tissue extracted by bronchoscopic cryobiopsy (CB was significantly higher compared to other standard biopsy techniques. This prospective, randomized, multicenter, single blinded study evaluates the accuracy of molecular genetic characterization of NSCLC for different cell sampling techniques. Key inclusion criteria are suspected lung cancer or the suspected relapse of known NSCLC that is bronchoscopically visible. Patients will be randomized, either to have a CB or a bronchoscopic forceps biopsy (FB). If indicated, a transbronchial needle aspiration (TBNA) of suspect lymph nodes will be performed. Blood liquid biopsy will be taken before tissue biopsy. The primary endpoint is the detection rate of molecular genetic alterations in NSCLC, using CB and FB. Secondary endpoints are differences in the combined detection of molecular genetic alterations between FB and CB, TBNA and liquid biopsy. This trial plans to recruit 540 patients, with 178 evaluable patients per study cohort. A histopathological and molecular genetic evaluation will be performed by the affiliated pathology departments of the national network for genomic medicine in lung cancer (nNGM), Germany. We will compare the diagnostic value of solid tumor tissue, lymph node cells and liquid biopsy for the molecular genetic characterization of NSCLC. This reflects a real world clinical setting, with potential direct impact on both treatment and survival

Epitheloide, biphasische und Mischtumoren des Weichgewebes

Epithelioid soft tissue tumors consist exclusively of epithelioid tumor cells. Biphasic tumors are composed of both aspindle-cell and an epithelioid component. The rare mixed tumors of soft tissue show abroader variety of cellular and stromal differentiation but also include at least one, possibly several, epithelioid portions.The close morphological similarity of some of these entities with each other, as well as with the more frequent soft tissue metastases of carcinomas, carcinosarcomas, and melanomas, to malignant mesothelioma and certain lymphomas, can often make the correct diagnosis extremely difficult. Recent advances in the detection of certain molecular alterations (mostly chromosomal translocations) have contributed to changes in tumor classification but also to improved pathological diagnostics (e.g. through the development of potent diagnostic antibodies) and biological understanding.The present overview should help the pathologist in the diagnosis of these rare tumors through the classical approach of morphological pattern recognition. The most important entities are discussed and illustrated in more detail, with the incorporation of the latest immunohistochemical and molecular aspects and the differential diagnosis of similar tumors

Rundzellige Sarkome

Round-cell sarcomas represent highly malignant tumors that occur predominantly in children, adolescents, and young adults. Round-cell sarcomas are caused by recurrent translocations that involve certain transcription factors. Ewing's sarcoma, Ewing-like sarcomas (e.g. CIC-DUX positive or BCOR positive sarcomas), desmoplastic small round-cell tumors (DSRCTs), and alveolar rhabdomyosarcomas (ARMs) are typical examples of this particular group of sarcomas. These entities differ in their tumor genetics, which is correlated with immunohistochemical expression profiles and with clinical phenotypes. Classification should be based on molecular findings. Immunohistochemistry may serve as a surrogate marker

Automated density-based counting of FISH amplification signals for HER2 status assessment

Background: Automated image analysis can make quantification of FISH signals in histological sections more efficient and reproducible. Current detection-based methods, however, often fail to accurately quantify densely clustered FISH signals. Methods: We propose a novel density-based approach to quantifying FISH signals. Instead of detecting individual signals, this approach quantifies FISH signals in terms of the integral over a density map predicted by Deep Learning. We apply the density-based approach to the task of counting and determining ratios of ERBB2 and CEN17 signals and compare it to common detection-based and area-based approaches. Results: The ratios determined by our approach were strongly correlated with results obtained by manual annotation of individual FISH signals (Pearson's r = 0.907). In addition, they were highly consistent with cutoff-scores determined by a pathologist (balanced concordance = 0.971). The density-based approach generally outperformed the other approaches. Its superiority was particularly evident in the presence of dense signal clusters. Conclusions: The presented approach enables accurate and efficient automated quantification of FISH signals. Since signals in clusters can hardly be detected individually even by human observers, the density-based quantification performs better than detection-based approaches

Development of high-risk HPV associated cervical dysplasia despite HPV-vaccination: a regional dysplasia center cohort study

The present study was conducted to examine the frequency of CIN/squamous intraepithelial lesions in patients after vaccination and respective HPV types observed at their referral to a regional center for screening of cervical dysplasia

Complexity of PEComas

Perivascular epithelioid cell neoplasms (PEComas) are a family of mesenchymal neoplasms with features of both melanotic and smooth muscle differentiation. PEComa morphology is highly variable and encompasses epithelioid to spindle cells often with clear cytoplasm and prominent nucleoli. Molecularly, most PEComas are defined by a loss of function of the TSC1/TSC2 complex. Additionally, a distinct small subset of PEComas harboring rearrangements of theTFE3(Xp11) gene locus has been identified. By presenting a series of three case reports with distinct features, we demonstrate diagnostic pitfalls as well as the importance of molecular work-up of PEComas because of important therapeutic consequences

Komplexität von PEComen

Perivascular epithelioid cell neoplasms (PEComas) are afamily of mesenchymal neoplasms with features of both melanotic and smooth muscle differentiation. PEComa morphology is highly variable and encompasses epithelioid to spindle cells often with clear cytoplasm and prominent nucleoli. Molecularly, most PEComas are defined by aloss of function of the TSC1/TSC2 complex. Additionally, adistinct small subset of PEComas harboring rearrangements of the TFE3 (Xp11) gene locus has been identified. By presenting aseries of three case reports with distinct features, we demonstrate diagnostic pitfalls as well as the importance of molecular work-up of PEComas because of important therapeutic consequences