K.W. Schmid

HER2 expression and markers of phosphoinositide-3-kinase pathway activation define a favorable subgroup of metastatic pulmonary adenocarcinomas

OBJECTIVES Pulmonary adenocarcinomas (ADC) can be sub-grouped based on dominant oncogenic drivers. EGFR mutations define an entity of metastatic ADC with favorable prognosis and high susceptibility to EGFR tyrosine kinase inhibition. In contrast, the clinical impact of additional ERBB family members in ADC is less defined. To this end we prospectively studied HER2 expression, gene amplification, and mutation in relation to outcome of patients with advanced or metastatic ADC. MATERIALS AND METHODS Diagnostic tumor biopsies from 193 sequential patients with stage III/IV ADC were prospectively studied for HER2 expression by immunohistochemistry (IHC). Cases with IHC scores 2+ or 3+ were analyzed by HER2 chromogenic in situ hybridization (CISH), and sequencing of HER2 exons 20 and 23. Additional prospectively determined biomarkers included PTEN, cMET, pAKT, and pERK expression, KRAS, EGFR, BRAF and PIK3CA mutations, and ALK fluorescence ISH (FISH). RESULTS AND CONCLUSION HER2-IHC was feasible in 176 (91.2%) cases. Of 53 (30%) cases with IHC scores 2+/3+, 45 (85%) could be studied by CISH and 34 (64%) by sequencing. The lower number of HER2-mutational analyses resulted from exhaustion of tumor tissue and DNA following mutational analysis of KRAS, EGFR, BRAF and PIK3CA. HER2 amplification was detected in 4 cases (2.3%), while no mutation was found. HER2 expression correlated with expression of pAKT and cMET. Expression of HER2 and pAKT was associated with favorable overall survival in stage IV disease. HER2-expressing ADC more frequently harbored KRAS mutations, while HER2 expression was absent in all 4 cases with BRAF mutation. HER2-IHC was not predictive of HER2 gene amplification or mutation, which both were rare events in prospectively studied patients with advanced or metastatic ADC. Expression of HER2 and pAKT define a population of patients with stage IV ADC with a distinct disease course, who could benefit from specifically tailored pharmacotherapies.

[Rapid on-site evaluation (ROSE) in cytological diagnostics of pulmonary and mediastinal diseases].

Endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-TBNA) has become an important tool in the diagnosis and staging of malignant tumors of the lungs and mediastinum. Rapid on-site evaluation (ROSE) denotes a cytomorphological diagnostic procedure that allows assessment of the adequacy and accuracy of the material obtained during bronchoscopy within a few minutes in or near the bronchoscopy suite (on-site) using a quick staining of smears. This results in a significant decrease in the number of repeated bronchoscopy procedures required to recover an adequate biopsy sample and is therefore both time and cost effective. The obtained material can be further assessed as conventional cytological specimens or alternatively using the thin-prep technique for definitive cytopathology diagnosis and/or embedded in paraffin for immunohistochemical or molecular analyses such as DNA sequencing or flow cytometry.

Hyalinizing trabecular tumor of the thyroid. An overcautious designation of a benign thyroid tumour

ZusammenfassungDer hyalinisierende trabekuläre Tumor der Schilddrüse ist ein seltener Tumor, der von den Follikelepithelzellen der Schilddrüse ausgeht und durch eine prominente intratrabekuläre Hyalinisierung gekennzeichnet ist. Aufgrund des Wachstumsmusters besteht eine Ähnlichkeit zum medullären Schilddrüsenkarzinom. Auffällige Kernatypien wie Kerninklusionen lassen an ein papilläres Schilddrüsenkarzinom denken. Deswegen ist die Dignitätsbeurteilung nach wie vor umstritten. Nachdem er aufgrund eindeutig fehlender Malignitätskriterien initial als Tumor mit benignem Verhalten eingestuft wurde, führten erste molekularpathologische Untersuchungen (Nachweis eines RET / PTC-Rearrangements) zu der Annahme, dass es sich um eine Variante des papillären Schilddrüsenkarzinoms handeln könnte. Neuere molekularpathologische Methoden wie die Bestimmung der microRNA, kurzer, nichtkodierender RNA, widerlegen jedoch diese Annahme. Der vorliegende Beitrag fasst die zur Diagnose wichtigen histomorphologischen Kriterien einschließlich neuer molekularpathologischer Erkenntnisse zusammen.AbstractHyalinizing trabecular tumours of the thyroid represent a rare entity of follicular cell derived tumours and are characterized by a marked intratrabecular hyalinisation. These tumours share architectural similarities with medullary thyroid carcinomas and exhibit nuclear features such as nuclear pseudoinclusions resembling papillary thyroid carcinoma. However, the clinical behaviour remains unclear. On the basis of their inconspicuous appearance and absence of invasion or recurrence during follow-up, the tumour was initially classified as an adenoma. Subsequently, molecular findings such as the detection of RET / PTC rearrangements in some hyalinizing trabecular tumours favoured the designation as a variant of papillary thyroid carcinoma. However, miRNA profiling of hyalinizing trabecular tumours compared with benign thyroid lesions and papillary thyroid carcinoma failed to demonstrate the characteristic up-regulation found in papillary thyroid carcinoma. This article summarizes conventional diagnostic criteria with supplementary information regarding molecular pathogenesis of hyalinizing trabecular tumours of the thyroid.Hyalinizing trabecular tumours of the thyroid represent a rare entity of follicular cell derived tumours and are characterized by a marked intratrabecular hyalinisation. These tumours share architectural similarities with medullary thyroid carcinomas and exhibit nuclear features such as nuclear pseudoinclusions resembling papillary thyroid carcinoma. However, the clinical behaviour remains unclear. On the basis of their inconspicuous appearance and absence of invasion or recurrence during follow-up, the tumour was initially classified as an adenoma. Subsequently, molecular findings such as the detection of RET / PTC rearrangements in some hyalinizing trabecular tumours favoured the designation as a variant of papillary thyroid carcinoma. However, miRNA profiling of hyalinizing trabecular tumours compared with benign thyroid lesions and papillary thyroid carcinoma failed to demonstrate the characteristic up-regulation found in papillary thyroid carcinoma. This article summarizes conventional diagnostic criteria with supplementary information regarding molecular pathogenesis of hyalinizing trabecular tumours of the thyroid.

Folic acid phenotype (FAP) is a superior biomarker predicting response to pemetrexed-based chemotherapy in malignant pleural mesothelioma

Background Malignant pleural mesothelioma (MPM) is a rare tumor linked to a dismal prognosis. Even the most effective chemotherapeutical regime of pemetrexed combined with cisplatin leads to a remission-rate of only about 40%. The reasons for the rather poor efficacy remain largely unknown. Results Phenotypes were significantly associated with progression (p=0.0279) and remission (p=0.0262). Cox-regression revealed significant associations between SLC19A1/TYMS-ratio (p=0.0076) as well as FPGS/TYMS-ratio (p=0.0026) and OS. For differentiation by risk-groups, COXPH identified a strong correlation (p=0.0008). Methods 56 MPM specimens from patients treated with pemetrexed were used for qPCR analysis. Phenotypes and risk groups were defined by their expression levels of members of the folic acid metabolism and correlated to survival and objective response. Conclusion Our results indicate that the balance between folic acid uptake, activation and metabolism plays a crucial role in response to pemetrexed-based chemotherapy and the prognosis of MPM patients. Implementing this marker profile in MPM stratification may help to individualize MPM-therapy more efficiently.

Glanduläres Papillom des rechten Hauptbronchus

ZusammenfassungBenigne epitheliale Tumoren des Tracheobronchialsystems und der Lunge sind seltene Neoplasien. Diese Entitäten umfassen plattenepitheliale und glanduläre Papillome (und deren Mischformen) sowie Adenome (Alveolaradenome, papilläre Adenome, speicheldrüsenartige pleomorphe und muzinöse Adenome sowie muzinöse Zystadenome). Die glandulären Papillome werden biologisch als benigne eingestuft. Bei intraoperativen Gefrierschnittuntersuchungen können jedoch erhebliche diagnostische Probleme in der Abgrenzung zu malignen Prozessen, insbesondere zu gut differenzierten papillären Adenokarzinomen, auftreten. Aufgrund des äußerst seltenen Vorkommens des glandulären Papilloms existieren bis dato nur einzelne deskriptive Untersuchungen dieser Neoplasien der unteren Atemwege. Eine systematische umfassende Aufarbeitung fehlt bislang ebenso wie molekularbiologischen Daten. Im vorliegenden Artikel wird der Fall einer 64-jährigen Patientin mit einem glandulären Papillom des rechten Hauptbronchus mit immunhistochemischer und molekularbiologischer Aufarbeitung dargestellt und ein Literaturüberblick gegeben.AbstractBenign epithelial tumors of the tracheobronchial system and the lungs are exceedingly rare. These entities encompass squamous and glandular papillomas (as well as their mixed forms) and adenomas (alveolar adenoma, papillary adenoma, salivary gland-like pleomorphic and mucinous adenomas and mucinous cystadenomas). These tumors are considered to be biologically benign neoplasms; however, they can pose considerable diagnostic difficulties, especially during frozen section evaluation, as they can mimic malignant tumors and in particular they can resemble well differentiated papillary adenocarcinomas. As a result of the extreme rarity of these tumors only a few descriptive diagnostic series exist and a systematic investigation including molecular data does not exist. This article presents the case of a 64-year-old patient with a glandular papilloma of the right main bronchus including the immunohistochemical and molecular work-up as well as a review of the current literature.Benign epithelial tumors of the tracheobronchial system and the lungs are exceedingly rare. These entities encompass squamous and glandular papillomas (as well as their mixed forms) and adenomas (alveolar adenoma, papillary adenoma, salivary gland-like pleomorphic and mucinous adenomas and mucinous cystadenomas). These tumors are considered to be biologically benign neoplasms; however, they can pose considerable diagnostic difficulties, especially during frozen section evaluation, as they can mimic malignant tumors and in particular they can resemble well differentiated papillary adenocarcinomas. As a result of the extreme rarity of these tumors only a few descriptive diagnostic series exist and a systematic investigation including molecular data does not exist. This article presents the case of a 64-year-old patient with a glandular papilloma of the right main bronchus including the immunohistochemical and molecular work-up as well as a review of the current literature.

Rapid and Highly Sensitive Detection of Therapeutically Relevant Oncogenic Driver Mutations in EBUS-TBNA Specimens From Patients With Lung Adenocarcinoma

&NA; We compared light cycler reverse transcription polymerase chain reaction (LCRT‐PCR) and next generation sequencing (NGS) to detect exon 19 deletion of epidermal growth factor receptor (EGFRdelEx19) and Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) exon 2 mutations in endobronchial ultrasound‐guided transbronchial needle aspirations (EBUS‐TBNAs). LCRT‐PCR additionally detected 2 KRAS exon 2 mutations and 3 EGFRdelEx19 mutations that were not detected using NGS. LCRT‐PCR is a highly sensitive method to rapidly detect mutations of therapeutic relevance. Background: First‐line afatinib treatment prolongs overall survival in patients with metastatic non–small‐cell lung cancer (NSCLC) harboring exon 19 deletion of epidermal growth factor receptor (EGFRdelEx19) mutations. In contrast, Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) mutations are negative predictors for benefit from EGFR‐targeting agents. Endobronchial ultrasound‐guided transbronchial needle aspiration (EBUS‐TBNA) is well‐established for lung cancer diagnosis and staging. Next generation sequencing (NGS) allows for simultaneous interrogation for multiple mutations but has limitations (required tumor tissue amount, assay times). Reverse transcription polymerase chain reaction (RT‐PCR) using light‐Cycler technology (LCRT‐PCR) can rapidly and sensitively detect somatic mutations from NSCLC patients. In the present study, we analyzed the feasibility of LCRT‐PCR for rapid EGFRdelEx19 and KRAS exon 2 mutation detection in EBUS‐TBNA samples and compared the LCRT‐PCR and NGS results. Materials and Methods: A total of 48 EBUS‐TBNA samples from 47 patients with a confirmed diagnosis of pulmonary adenocarcinoma were analyzed using LCRT‐PCR (as previously described) and NGS (MiSeq; Illumina) using targeted resequencing and a customized multiplex PCR panel. The processing time was ˜1 week for the NGS and < 24 hours for the LCRT‐PCR analyses. Results: All (100%) EGFRdelEx19 and KRAS exon 2 mutations detected by NGS were detected by LCRT‐PCR. In addition, LCRT‐PCR detected 2 KRAS exon 2 mutations and 3 EGFRdelEx19 mutations that were not detected by NGS. Conclusion: LCRT‐PCR is a highly sensitive method to rapidly detect mutations of therapeutic relevance (eg, EGFRdelEx19 and KRAS exon 2) in EBUS‐TBNAs from NSCLC patients. It is of value as an initial assay for first‐line treatment decisions.

Glanduläres Papillom des rechten Hauptbronchus@@@Glandular papilloma of the right main bronchus: Nachweis einer Exon-2-Mutation des KRAS-Gens (c.35G>A)@@@Detection of an exon 2 mutation of the KRAS gene (c.35G>A)

ZusammenfassungBenigne epitheliale Tumoren des Tracheobronchialsystems und der Lunge sind seltene Neoplasien. Diese Entitäten umfassen plattenepitheliale und glanduläre Papillome (und deren Mischformen) sowie Adenome (Alveolaradenome, papilläre Adenome, speicheldrüsenartige pleomorphe und muzinöse Adenome sowie muzinöse Zystadenome). Die glandulären Papillome werden biologisch als benigne eingestuft. Bei intraoperativen Gefrierschnittuntersuchungen können jedoch erhebliche diagnostische Probleme in der Abgrenzung zu malignen Prozessen, insbesondere zu gut differenzierten papillären Adenokarzinomen, auftreten. Aufgrund des äußerst seltenen Vorkommens des glandulären Papilloms existieren bis dato nur einzelne deskriptive Untersuchungen dieser Neoplasien der unteren Atemwege. Eine systematische umfassende Aufarbeitung fehlt bislang ebenso wie molekularbiologischen Daten. Im vorliegenden Artikel wird der Fall einer 64-jährigen Patientin mit einem glandulären Papillom des rechten Hauptbronchus mit immunhistochemischer und molekularbiologischer Aufarbeitung dargestellt und ein Literaturüberblick gegeben.AbstractBenign epithelial tumors of the tracheobronchial system and the lungs are exceedingly rare. These entities encompass squamous and glandular papillomas (as well as their mixed forms) and adenomas (alveolar adenoma, papillary adenoma, salivary gland-like pleomorphic and mucinous adenomas and mucinous cystadenomas). These tumors are considered to be biologically benign neoplasms; however, they can pose considerable diagnostic difficulties, especially during frozen section evaluation, as they can mimic malignant tumors and in particular they can resemble well differentiated papillary adenocarcinomas. As a result of the extreme rarity of these tumors only a few descriptive diagnostic series exist and a systematic investigation including molecular data does not exist. This article presents the case of a 64-year-old patient with a glandular papilloma of the right main bronchus including the immunohistochemical and molecular work-up as well as a review of the current literature.Benign epithelial tumors of the tracheobronchial system and the lungs are exceedingly rare. These entities encompass squamous and glandular papillomas (as well as their mixed forms) and adenomas (alveolar adenoma, papillary adenoma, salivary gland-like pleomorphic and mucinous adenomas and mucinous cystadenomas). These tumors are considered to be biologically benign neoplasms; however, they can pose considerable diagnostic difficulties, especially during frozen section evaluation, as they can mimic malignant tumors and in particular they can resemble well differentiated papillary adenocarcinomas. As a result of the extreme rarity of these tumors only a few descriptive diagnostic series exist and a systematic investigation including molecular data does not exist. This article presents the case of a 64-year-old patient with a glandular papilloma of the right main bronchus including the immunohistochemical and molecular work-up as well as a review of the current literature.

[Glandular papilloma of the right main bronchus. Detection of an exon 2 mutation of the KRAS gene (c.35G>A)].

ZusammenfassungBenigne epitheliale Tumoren des Tracheobronchialsystems und der Lunge sind seltene Neoplasien. Diese Entitäten umfassen plattenepitheliale und glanduläre Papillome (und deren Mischformen) sowie Adenome (Alveolaradenome, papilläre Adenome, speicheldrüsenartige pleomorphe und muzinöse Adenome sowie muzinöse Zystadenome). Die glandulären Papillome werden biologisch als benigne eingestuft. Bei intraoperativen Gefrierschnittuntersuchungen können jedoch erhebliche diagnostische Probleme in der Abgrenzung zu malignen Prozessen, insbesondere zu gut differenzierten papillären Adenokarzinomen, auftreten. Aufgrund des äußerst seltenen Vorkommens des glandulären Papilloms existieren bis dato nur einzelne deskriptive Untersuchungen dieser Neoplasien der unteren Atemwege. Eine systematische umfassende Aufarbeitung fehlt bislang ebenso wie molekularbiologischen Daten. Im vorliegenden Artikel wird der Fall einer 64-jährigen Patientin mit einem glandulären Papillom des rechten Hauptbronchus mit immunhistochemischer und molekularbiologischer Aufarbeitung dargestellt und ein Literaturüberblick gegeben.AbstractBenign epithelial tumors of the tracheobronchial system and the lungs are exceedingly rare. These entities encompass squamous and glandular papillomas (as well as their mixed forms) and adenomas (alveolar adenoma, papillary adenoma, salivary gland-like pleomorphic and mucinous adenomas and mucinous cystadenomas). These tumors are considered to be biologically benign neoplasms; however, they can pose considerable diagnostic difficulties, especially during frozen section evaluation, as they can mimic malignant tumors and in particular they can resemble well differentiated papillary adenocarcinomas. As a result of the extreme rarity of these tumors only a few descriptive diagnostic series exist and a systematic investigation including molecular data does not exist. This article presents the case of a 64-year-old patient with a glandular papilloma of the right main bronchus including the immunohistochemical and molecular work-up as well as a review of the current literature.Benign epithelial tumors of the tracheobronchial system and the lungs are exceedingly rare. These entities encompass squamous and glandular papillomas (as well as their mixed forms) and adenomas (alveolar adenoma, papillary adenoma, salivary gland-like pleomorphic and mucinous adenomas and mucinous cystadenomas). These tumors are considered to be biologically benign neoplasms; however, they can pose considerable diagnostic difficulties, especially during frozen section evaluation, as they can mimic malignant tumors and in particular they can resemble well differentiated papillary adenocarcinomas. As a result of the extreme rarity of these tumors only a few descriptive diagnostic series exist and a systematic investigation including molecular data does not exist. This article presents the case of a 64-year-old patient with a glandular papilloma of the right main bronchus including the immunohistochemical and molecular work-up as well as a review of the current literature.

Der hyalinisierende trabekuläre Tumor der Schilddrüse@@@Hyalinizing trabecular tumor of the thyroid: Eine übertrieben vorsichtige Bezeichnung für einen gutartigen Tumor?@@@An overcautious designation of a benign thyroid tumour?

ZusammenfassungDer hyalinisierende trabekuläre Tumor der Schilddrüse ist ein seltener Tumor, der von den Follikelepithelzellen der Schilddrüse ausgeht und durch eine prominente intratrabekuläre Hyalinisierung gekennzeichnet ist. Aufgrund des Wachstumsmusters besteht eine Ähnlichkeit zum medullären Schilddrüsenkarzinom. Auffällige Kernatypien wie Kerninklusionen lassen an ein papilläres Schilddrüsenkarzinom denken. Deswegen ist die Dignitätsbeurteilung nach wie vor umstritten. Nachdem er aufgrund eindeutig fehlender Malignitätskriterien initial als Tumor mit benignem Verhalten eingestuft wurde, führten erste molekularpathologische Untersuchungen (Nachweis eines RET / PTC-Rearrangements) zu der Annahme, dass es sich um eine Variante des papillären Schilddrüsenkarzinoms handeln könnte. Neuere molekularpathologische Methoden wie die Bestimmung der microRNA, kurzer, nichtkodierender RNA, widerlegen jedoch diese Annahme. Der vorliegende Beitrag fasst die zur Diagnose wichtigen histomorphologischen Kriterien einschließlich neuer molekularpathologischer Erkenntnisse zusammen.AbstractHyalinizing trabecular tumours of the thyroid represent a rare entity of follicular cell derived tumours and are characterized by a marked intratrabecular hyalinisation. These tumours share architectural similarities with medullary thyroid carcinomas and exhibit nuclear features such as nuclear pseudoinclusions resembling papillary thyroid carcinoma. However, the clinical behaviour remains unclear. On the basis of their inconspicuous appearance and absence of invasion or recurrence during follow-up, the tumour was initially classified as an adenoma. Subsequently, molecular findings such as the detection of RET / PTC rearrangements in some hyalinizing trabecular tumours favoured the designation as a variant of papillary thyroid carcinoma. However, miRNA profiling of hyalinizing trabecular tumours compared with benign thyroid lesions and papillary thyroid carcinoma failed to demonstrate the characteristic up-regulation found in papillary thyroid carcinoma. This article summarizes conventional diagnostic criteria with supplementary information regarding molecular pathogenesis of hyalinizing trabecular tumours of the thyroid.Hyalinizing trabecular tumours of the thyroid represent a rare entity of follicular cell derived tumours and are characterized by a marked intratrabecular hyalinisation. These tumours share architectural similarities with medullary thyroid carcinomas and exhibit nuclear features such as nuclear pseudoinclusions resembling papillary thyroid carcinoma. However, the clinical behaviour remains unclear. On the basis of their inconspicuous appearance and absence of invasion or recurrence during follow-up, the tumour was initially classified as an adenoma. Subsequently, molecular findings such as the detection of RET / PTC rearrangements in some hyalinizing trabecular tumours favoured the designation as a variant of papillary thyroid carcinoma. However, miRNA profiling of hyalinizing trabecular tumours compared with benign thyroid lesions and papillary thyroid carcinoma failed to demonstrate the characteristic up-regulation found in papillary thyroid carcinoma. This article summarizes conventional diagnostic criteria with supplementary information regarding molecular pathogenesis of hyalinizing trabecular tumours of the thyroid.

„Rapid on-site evaluation“ (ROSE) in der zytologischen Diagnostik von Lungen- und Mediastinalerkrankungen@@@Rapid on-site evaluation (ROSE) in cytological diagnostics of pulmonary and mediastinal diseases

Endobronchial ultrasound-guided transbronchial fine needle aspiration (EBUS-TBNA) has become an important tool in the diagnosis and staging of malignant tumors of the lungs and mediastinum. Rapid on-site evaluation (ROSE) denotes a cytomorphological diagnostic procedure that allows assessment of the adequacy and accuracy of the material obtained during bronchoscopy within a few minutes in or near the bronchoscopy suite (on-site) using a quick staining of smears. This results in a significant decrease in the number of repeated bronchoscopy procedures required to recover an adequate biopsy sample and is therefore both time and cost effective. The obtained material can be further assessed as conventional cytological specimens or alternatively using the thin-prep technique for definitive cytopathology diagnosis and/or embedded in paraffin for immunohistochemical or molecular analyses such as DNA sequencing or flow cytometry.