Everolimus with paclitaxel and carboplatin as first-line treatment for metastatic large-cell neuroendocrine lung carcinoma: a multicenter phase II trial.

BACKGROUND: Large-cell neuroendocrine carcinoma of the lung (LCNEC) is a rare disease with poor prognosis and limited treatment options. Neuroendocrine tumors frequently show overactivation of the mTOR pathway. Based on the good activity of the mTOR inhibitor everolimus in different types of neuroendocrine tumors and the results of a previous phase I trial, we evaluated the efficacy and safety of everolimus in combination with carboplatin and paclitaxel as upfront treatment for patients with advanced LCNEC. PATIENTS AND METHODS: In this prospective, multicenter phase II trial chemotherapy-naive patients with stage IV LCNEC received 5 mg everolimus daily combined with paclitaxel 175 mg/m2 and carboplatin AUC 5 every 3 weeks for a maximum of four cycles followed by maintenance everolimus 5 mg daily until progression. Efficacy parameters were determined based on central radiologic assessment. RESULTS: Forty-nine patients with a mean age of 62 ±9 years and a predominance of male (71%) smokers (98%) were enrolled in 10 German centers. The overall response rate was 45% (95% confidence interval [CI] 31%-60%), the disease control rate 74% (CI 59%-85%), the median progression-free survival 4.4 (CI 3.2-6) months and the median overall survival 9.9 (CI 6.9-11.7) months. The progression-free survival rate at 3 months (primary end point) was 76% (CI 64%-88%) according to Kaplan-Meier. Grade-3/4 toxicities occurred in 51% of patients and mainly consisted of general physical health deterioration (8%), cytopenias (24%), infections (10%) and gastrointestinal problems (8%). Typical everolimus-related adverse events, like stomatitis, rash and ocular problems occurred only in a minority of patients (<15%) and were exclusively of grade 1-2. CONCLUSION: Everolimus in combination with carboplatin and paclitaxel is an effective and well-tolerated first-line treatment for patients with metastatic LCNEC. REGISTERED CLINICAL TRIAL NUMBERS: EudraCT number 2010-022273-34, NCT01317615.

[Grading of lung cancer]. / Grading von Lungenkarzinomen.

In comparison with other tumor entities there is no common generally accepted grading system for lung cancer with clearly defined criteria and clinical relevance. In the recent fourth edition of the World Health Organization (WHO) classification from 2015 of tumors of the lungs, pleura, thymus and heart, there is no generally applicable grading for pulmonary adenocarcinomas, squamous cell carcinomas or rarer forms of carcinoma. Since the new IASLC/ATS/ERS classification of adenocarcinomas published in 2011, 5 different subtypes with significantly different prognosis are proposed. This results in an architectural (histologic) grading, which is usually applied to resection specimens. For squamous cell carcinoma the number of different histological subtypes in the new WHO classification was reduced compared to earlier versions but without a common grading system. In recent publications nesting and budding were proposed as the main (histologic) criteria for a grading of squamous cell carcinomas. The grading of neuroendocrine tumors (NET) of the lungs in comparison with NET in other organs is presented in a separate article in this issue. Certain rare tumor types are high grade per definition: small cell, large cell and pleomorphic carcinomas, carcinosarcomas and pulmonary blastomas. In the future it is to be expected that these developments will be further refined, e. g. by adding further subtypes for adenocarcinomas and cytologic and/or nuclear criteria for adenocarcinoma and/or squamous cell carcinomas.

[Grading of neuroendocrine tumors]. / Grading neuroendokriner Tumoren.

The current WHO classification of neuroendocrine tumors (NET) differentiates between typical carcinoids (low grade NET), atypical carcinoids (intermediate grade NET) and small cell and large cell carcinomas (high grade NET) according to the prognosis. Neuroendocrine neoplasms (NEN) of the gastrointestinal tract and the pancreas are graded in an identical way. Together with the TNM system this enables a preoperative estimation of the prognosis in biopsies and fine needle aspirates. Well-differentiated tumors are graded into G1 tumors by the number of mitoses, <2 per 10 high-power fields (HPF) and the Ki-67 (index <3 %) and G2 tumors (2-20 mitoses/10 HPF, Ki-67 3-20 %). Discrepancies between the number of mitoses and the Ki-67 index are not uncommon and in these cases the higher value of the two should be applied. The more differentiated tumors of the G3 type have to be differentiated from undifferentiated carcinomas of the small cell type and large cell type with a much poorer prognosis. Prognosis relevant grading of thyroid cancers is achieved by special subtyping so that the G1-G3 system is not applicable. The rare cancers of the parathyroid gland and of the pituitary gland are not graded. Adrenal tumors also have no grading system. The prognosis is dependent on the Ki-67 index and with some reservations on the established scoring systems.

[Application and interpretation of the R classification for lung cancer : Results of a survey of certified lung cancer centers]. / Anwendung und Interpretation der R­Klassifikation beim Lungenkarzinom : Ergebnisse einer Umfrage an zertifizierten Lungenkrebszentren.

The residual (R) tumor classification is an essential, even if facultative component of the TNM classification; however, it should alway be included in the pathology results of certified lung cancer centers. In discussions it becomes clear again and again that different hospitals and departments have different approaches and interpretations with respect to the R status after lung resection. We carried out a questionnaire-based survey of pathologists (with specialization in pulmonary pathology) and thoracic surgeons on the application of the R classification for lung tumors. The results of the survey revealed the different perceptions of the participating centers with respect to application and interpretation, which results in divergent decisions for adjuvant therapy and complicates the comparability of national and international studies. The results of the survey are especially valuable because all participants have a high level of expertise in the field of thoracic pathology and the data reflect the current practice in certified lung cancer centers. It appears to be necessary to examine the application and interpretation of the R classification for lung cancer more closely in an interdisciplinary exchange and to produce a catalogue of criteria to guarantee at least a better national standardization.

Application in Europe of a urine-based rapid diagnostic test for confirmation of Schistosoma mansoni infection in migrants from endemic areas.

In February 2015, a male patient from Eritrea with persistent abdominal pain and rectal bleeding was diagnosed with Schistosoma mansoni infection upon examination of a rectal biopsy. In May 2015, repeated stool microscopy identified S. mansoni infection in another Eritrean patient with abdominal pain and considerable eosinophilia (34%). Use of point-of-care circulating cathodic antigen (POC-CCA) tests on urine confirmed S. mansoni infection in both patients. Wider application of non-invasive POC-CCA urine tests will improve schistosomiasis diagnosis and clinical management in migrants.

[Pulmonary neuroendocrine tumors in the new WHO 2015 classification: Start of breaking new grounds?]. / Pulmonale neuroendokrine Tumoren in der neuen WHO-Klassifikation 2015 : Beginn eines Aufbruchs zu "neuen Ufern"?

CLASSIFICATION: In the recently published 4th edition of the World Health Organization (WHO) classification of tumors of the lungs, pleura, thymus and heart, all neuroendocrine tumors of the lungs (pNET) are presented for the first time in one single chapter following adenocarcinoma and squamous cell carcinoma and before large cell carcinoma. In this classification, high grade small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are differentiated from intermediate grade atypical carcinoids (AC) and low grade typical carcinoids as well as from preinvasive lesions (DIPNECH). In the 3rd WHO classification from 2004, which dealt with resection specimens, SCLC and carcinoids each had a separate chapter and LCNEC was previously listed in the chapter on large cell carcinoma of the lungs. The new WHO classification is for the first time also applicable to lung biopsies. DIAGNOSTICS: Normally, common features of all pNET are a neuroendocrine morphology (as far as detectable in small biopsies) and expression of the neuroendocrine (NE) markers (chromogranin A, synaptophysin and CD56/NCAM). An immunohistochemical positive staining of at least one NE marker was already recommended in the 3rd edition of the WHO classification (2004) only for LCNEC. Differentiating features are a small or large cell cytomorphology/histomorphology, nuclear criteria and the mitotic rate (for SCLC >10 with a median of 80, for LCNEC >10 median 70, for AC 2 - 10, for TC < 2 each per 2 mm(2)). Tumor cell necrosis usually occurs in SCLC and LCNEC, partially in AC and not in TC. The guideline Ki67 proliferation rates are given for the first time in the new WHO classification for SCLC as 50-100 %, for LCNEC 40-80 %, for AC up to 20 % and for TC up to 5 %. MOLECULAR PATHOLOGY: Molecular alterations occur in SCLC and LCNEC in large numbers and are very variable in quality. In AC and TC they occur much less frequently and are relatively similar. CONCLUSION: The direct comparison of all pNET in one chapter facilitates the differential diagnostics of these tumors, provides a better transparency especially of LCNEC and allows a further comprehensive development of the clinical practical and scientific evaluation of pNET. Although a separate terminology of pNET is maintained for the lungs, a careful approach towards the gastroentero-pancreatic NET (gepNET) can be observed.

Tumour cell proliferation (Ki-67) in non-small cell lung cancer: a critical reappraisal of its prognostic role.

BACKGROUND: Uncontrolled proliferation is a hallmark of malignant tumour growth. Its prognostic role in non-small cell lung cancer (NSCLC) has been investigated in numerous studies with controversial results. We aimed to resolve these controversies by assessing the Ki-67 proliferation index (PI) in three large, independent NSCLC cohorts. METHODS: Proliferation index was retrospectively analysed by immunohistochemistry in a cohort of 1065 NSCLC and correlated with clinicopathological data including outcome and therapy. RESULTS were validated in two independent cohorts of 233 squamous cell carcinomas (SQCC) and 184 adenocarcinomas (ADC). RESULTS: Proliferation index (overall mean: 40.7%) differed significantly according to histologic subtypes with SQCC showing a mean PI (52.8%) twice as high as ADC (25.8%). In ADC PI was tightly linked to growth patterns. In SQCC and ADC opposing effects of PI on overall (OS), disease-specific and disease-free survival were evident, in ADC high PI (optimised validated cut-off: 25%) was a stage-independent negative prognosticator (hazard ratio, HR OS: 1.56, P=0.004). This prognostic effect was largely attenuated by adjuvant radio-/chemotherapy. In SQCC high PI (optimised validated cut-off: 50%) was associated with better survival (HR OS: 0.65, P=0.007). CONCLUSIONS: Our data demonstrate that PI is a clinically meaningful biomarker in NSCLC with entity-dependent cut-off values that allow reliable estimation of prognosis and may potentially stratify ADC patients for the need of adjuvant therapy.

[Neuroendocrine tumors of the lungs. From small cell lung carcinoma to diffuse idiopathic pulmonary neuroendocrine cell hyperplasia]. / Neuroendokrine Tumoren der Lunge. Vom kleinzelligen Lungenkarzinom bis zur diffusen idiopathischen pulmonalen neuroendokrinen Zellhyperplasie.

The new World Health Organization (WHO) classification announced for 2015 will for the first time present all neuroendocrine tumors (NET) of the lungs in one single section. In this classification high grade small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) will be discriminated from intermediate grade atypical carcinoid (AC) and low grade typical carcinoid as well as from the preinvasive lesion diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH). The LCNEC was previously listed under the section of large cell carcinomas. The LCNEC could previously be diagnosed according to the current WHO classification from 2004 which is designed for resection specimens. According to this the main diagnostic criteria are a neuroendocrine growth pattern which can be difficult or impossible to detect in biopsy material, non-small cell cytological features, more than 10 mitoses per 2 mm(2) (mean 70-80 per 2 mm(2)), tumor cell necrosis, and an immunohistochemical positivity for at least one neuroendocrine marker other than neuron-specific enolase (NSE). The presentation of all neuroendocrine tumors of the lungs in one section allows a more direct comparison and a better differential diagnostic discrimination of the different entities.

[Molecular pathological diagnosis in cytopathology of non-small-cell lung cancer. Standardization of specimen processing]. / Molekularpathologische Diagnostik in der Zytopathologie des nichtkleinzelligen Lungenkarzinoms. Standardisierung der Materialprozessierung.

BACKGROUND: Personalized medicine is becoming standard for the treatment of non-small-cell lung cancer. For example, patients with activating EGFR mutations or EML4-ALK translocations largely benefit from targeted therapies with tyrosine kinase inhibitors with better response rates and progression-free survival compared to standard chemotherapy regimens. However, the application of the respective molecular biomarker analyses requires great expertise in the handling of different cell and tissue specimens. A major challenge for reliable analyses is the usually low amount of tumor material. There are currently relatively few standardized and evidence-based guidelines for the processing and analysis of respective specimens as well as for interpretation of the test results. MATERIALS AND METHODS: To establish a basis for standardized predictive cytopathological analyses, different material processing approaches and molecular pathological tests are discussed, and novel concepts and strategies are lined out in order to improve the quality and reliability of the respective diagnostic procedures. RESULTS AND DISCUSSION: Predictive analyses of cytological specimens can be reliably performed using smears, cytospins or cell blocks; there is no need for histological specimens. The diagnostic work-up of cytological probes should be performed as carefully as possible in order to save further tumor material for subsequent predictive analyses. With standardized and reliable procedures at hand cytopathology is an important contribution to the multidisciplinary, complex care, and treatment of lung cancer patients.

[Familial pulmonary cysts and papular skin lesions in a 37-year-old woman]. / Familiäre pulmonale Zysten und papulöse Hauteffloreszenzen bei einer 37-jährigen Patientin.

A 37-year-old female patient presented with sudden dyspnea and chest pain. Spontaneous pneumothoraces had been observed several times before in this patient and two members of the patient´s family in the last years. Moreover, she exhibited papular facial skin lesions. Radiomorphologically a pneumothorax apical on the left side and basal accentuated cystic lung destruction on both sides could be seen. Pleurodesis and several wedge resections with insertion of a drainage on the left side were performed therapeutically. Histology disclosed multiple cysts, whereby typical differential diagnoses could be excluded by immunohistochemistry. A molecular genetic investigation detected a heterozygous mutation in the gene coding for follikulin (FLCN). Thereby, Birt-Hogg-Dubé syndrome (BHDS) was diagnosed. BHDS follows autosomal dominant inheritance and is characterized by cystic lung lesions with recurrent pneumothoraces, cutaneous fibrofolliculomas and an increased risk of renal carcinomas. It is based on mutations in the gene coding for the protein FLCN on chromosome 17.

[Diagnostic and predictive analyses of cytological specimens of non-small cell lung cancer: strategies and challenges]. / Diagnose und prädiktive Analysen an zytologischen und bioptischen Tumorproben nicht-kleinzelliger Lungenkarzinome: Aktuelle Strategien und Herausforderungen.

Personalised medicine is becoming the standard care for advanced non-small cell lung cancer. Tumour-specific therapies based on biomarker analyses, e. g., EGFR mutations or translocations of the ALK gene locus, result in a superior patient outcome compared to unselected therapy approaches. However, predictive molecular analyses can be challenging and require significant experience with cell- and tissue-based diagnostic methods. The major challenge relates to the sometimes low amount of available tumour material for both diagnostic and predictive analyses. As yet, there are no standardised or evidence-based recommendations concerning biopsies, specimen processing, and analyses. Respective guidelines require combined interdisciplinary actions to consider both clinical and pathological aspects. In order to establish a basis for high quality procedures, different approaches, methods, and protocols were interdisciplinary discussed with an emphasis on cytological specimens. Detailed evaluation of the parameters and consented recommendations might contribute to optimised strategies in the interdisciplinary, more and more complex care of non-small cell lung cancer patients.

Cryobiopsy increases the diagnostic yield of endobronchial biopsy: a multicentre trial.

Forceps, brushes or needles are currently the standard tools used during flexible bronchoscopy when diagnosing endobronchial malignancies. The new biopsy technique of cryobiopsy appears to provide better diagnostic samples. The aim of this study was to evaluate cryobiopsy over conventional endobronchial sampling. A total of 600 patients in eight centres with suspected endobronchial tumours were included in a prospective, randomised, single-blinded multicentre study. Patients were randomised to either sampling using forceps or the cryoprobe. After obtaining biopsy samples, a blinded histological evaluation was performed. According to the definitive clinical diagnosis, the diagnostic yield for malignancy was evaluated by a Chi-squared test. A total of 593 patients were randomised, of whom 563 had a final diagnosis of cancer. 281 patients were randomised to receive endobronchial biopsies using forceps and 282 had biopsies performed using a flexible cryoprobe. A definitive diagnosis was achieved in 85.1% of patients randomised to conventional forceps biopsy and 95.0% of patients who underwent cryobiopsy (p<0.001). Importantly, there was no difference in the incidence of significant bleeding. Endobronchial cryobiopsy is a safe technique with superior diagnostic yield in comparison with conventional forceps biopsy.

Simultaneous computed tomography-guided biopsy and radiofrequency ablation of solitary pulmonary malignancy in high-risk patients.

BACKGROUND: In recent years experience has been accumulated in percutaneous radiofrequency ablation (RFA) of lung malignancies in nonsurgical patients. OBJECTIVES: In this study, we retrospectively evaluated a simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions. METHODS: CT-guided transthoracic core needle biopsy of solitary pulmonary lesions suspicious for malignancy was performed and histology was proven based on immediate frozen sections. RFA probes were placed into the pulmonary tumors under CT guidance and the ablation was performed subsequently. The procedure-related morbidity was analyzed. Follow-up included a CT scan and pulmonary function parameters. RESULTS: A total of 33 CT-guided biopsies and subsequent RFA within a single procedure were performed. Morbidity of CT-guided biopsy included pulmonary hemorrhage (24%) and a mild pneumothorax (12%) without need for further interventions. The RFA procedure was not aggravated by the previous biopsy. The rate of pneumothorax requiring chest tube following RFA was 21%. Local tumor control was achieved in 77% with a median follow-up of 12 months. The morbidity of the CT-guided biopsy had no statistical impact on the local recurrence rate. CONCLUSIONS: The simultaneous diagnostic and therapeutic approach including CT-guided biopsy followed immediately by RFA of solitary malignant pulmonary lesions is a safe procedure. The potential of this combined approach is to avoid unnecessary therapies and to perform adequate therapies based on histology. Taking the local control rate into account, this approach should only be performed in those patients who are unable to undergo or who refuse surgery.

[What's new in lung pathology: minutes from the Pulmonary Pathology Working Group of the German Society of Pathology]. / Neues zur Lungenpathologie: Bericht der Arbeitsgemeinschaft Pneumopathologie der Deutschen Gesellschaft für Pathologie.

The pulmonary pathology working group was founded in 2008 and has been officially active since the 93(rd) Freiburg DGP ("Deutsche Gesellschaft für Pathologie", German Society of Pathology) congress in 2009. It is based on the competence and activity of its members who elect the board, the chair, and its vice chair. Both are responsible for the organization of the sessions at the annual DGP congress in the spring and a meeting in the fall. The vice chair will replace the chair after one year. The working group concentrates on scientific issues and topics relevant for daily practice, including solutions to specific diagnostic cases. This article highlights the history of the working group, the pulmonary sessions at the 95(th) DGP congress in Leipzig 2011, and future activities. New results for lung cancer from whole genome sequencing are addressed. Specifically, recent data is presented on FGFR1 amplification, DDR2 mutation, and EML4-ALK fusion, the role of non-coding RNA, cell adhesion, the cytoskeleton, as well as the problem of subtyping of lung tumors in cytology.

Current data on predictive markers for anti-angiogenic therapy in thoracic tumours.

The fact that growth and spread of tumours are dependent on angiogenesis has led to the investigation of the role of anti-angiogenic agents in the therapeutic strategies for thoracic tumours such as nonsmall cell lung cancer or mesotheliomas. Since various angiogenic factors may contribute to the regulation of angiogenesis in the individual tumour, in the era of increasing amounts of clinically tested agents it is of utmost importance to properly select patients that may benefit from a specific therapy. Due to the complex nature of tumour angiogenesis, various biomarkers may be applicable. For example, the profile of activated angiogenic pathways in endothelial cells may be determined in order to make conclusions about the relevance of inhibiting a given pathway by a selected agent. Moreover, changes in protein expression in stromal and tumour cells, as well as structural alterations in the vasculature, may be used for predicting and monitoring the clinical effects of such a therapy. In this review, the current data from clinical studies evaluating predictive markers for anti-angiogenic agents in thoracic cancers are summarised. Besides giving clinical examples, the rationales for investigating various parameters based on pre-clinical studies are described.

[S100 protein positive sustentacular cells in pulmonary carcinoids and thoracic paragangliomas: differential diagnostic and prognostic evaluation]. / S100-Protein-positive Sustentakularzellen in pulmonalen Karzinoiden und thorakalen Paragangliomen : Differenzialdiagnostische und prognostische Bedeutung.

Paragangliomas have a classical histomorphology comprising a so-called "Zellballen" or nesting pattern with surrounding S100 protein positive sustentacular cells (SC) which form a meshwork with a wire-fence appearance. In adrenal and extra-adrenal paragangliomas the prevalence of SC is inversely associated with the patients' outcome. In order to get more insight into the prevalence as well as the prognostic and differential diagnostic value of this cell population in pulmonary carcinoids, we investigated a panel of 26 tumorlets, 147 typical and atypical pulmonary carcinoids and ten thoracic paragangliomas immunohistochemically. We were able to demonstrate that S100 protein positive cells are similarly distributed in both thoracic paragangliomas and pulmonary carcinoids. Hence, the presence and distribution of these cells does not appear to represent a reliable criterion in differential diagnosis. Moreover, all pulmonary carcinoid patients with a worse outcome had low numbers of or no S100 protein positive cells in their tissue specimens. Thus, the prevalence of these cells may potentially aid in prognostic assessment of pulmonary carcinoids, especially in biopsies.

[Risk stratification and treatment of cardiac amyloidoses]. / Risikostratifizierung und Therapie kardialer Amyloidosen.

Cardiac amyloidoses are a heterogeneous group of cardiomyopathies that are resistant to treatment and are associated with a poor outcome. Standard heart failure treatment is usually not well tolerated and the underlying disease remains unaffected. The clinical picture is uncharacteristic. Cardiac amyloidosis is often associated with dysfunction of additional organs. Early cardiac amyloid involvement usually reveals left ventricular hypertrophy, impairment of longitudinal shortening and diastolic ventricular function. Without adequate therapy (bi-)ventricular hypertrophy will progress to severe systolic ventricular function decrease. The combination of low voltage pattern, left ventricular hypertrophy and granular sparkling is characteristic for advanced cardiac amyloid involvement. Cardiac magnetic resonance imaging and scintigraphy yield further information on the pattern and severity of cardiac involvement. In unclear cases (left ventricular) endomyocardial biopsy is necessary. Detection of early cardiac involvement and proper identification of patients at high risk for sudden cardiac death due to rapid progressive amyloidosis is still incompletely defined. Referral to specialized centers is strongly recommended.

Mediastinal angiomyolipomas in a male patient affected by tuberous sclerosis.

Classical angiomyolipomas are benign tumours composed of various tissues, including components of fat, abnormal blood vessels and smooth muscle cells. They are often found in association with tuberous sclerosis complex (TSC). The present study reports a male patient affected by TSC with intermittent, massive chylous pleural effusions, who developed recurrent mediastinal angiomyolipomas. The tumours were characterised via histological and immunohistochemical methods. Although angiomyolipomas frequently occur in the kidneys of TSC patients, this case is the first report of mediastinal angiomyolipomas associated with TSC. Besides lymphangioleiomyomatosis, this differential diagnosis has to be taken into account in the case of chylous pleural effusions and mediastinal masses in tuberous sclerosis complex patients.

Impact of apoptosis in acute rejection episodes after heart transplantation: immunohistochemical examination of right ventricular myocardial biopsies.

OBJECTIVE: Acute rejection may lead to cell death following heart transplantation. Programmed cell death (apoptosis) has been described as a cofactor for cell loss in cardiac tissue. The aim of our study was to quantify the amount and extent of apoptotic cells during acute rejection episodes after orthotopic heart transplantation. PATIENTS AND METHODS: Right ventricular biopsies from 27 heart transplant recipients were classified histologically according to rejection grade. Formalin-fixed sections were processed for immunohistochemistry. TUNEL-positive cells were counted and the expression of apoptosis-modulating factors Bax, Bcl-x(L), Bcl-2, and Ki-67 (proliferation marker) was scored. P