Small cell carcinoma of the lung and large cell neuroendocrine carcinoma interobserver variability

Department of Pathology, Erasmus MC, PO Box 2040, 3000 CA, Rotterdam, the Netherlands.
Histopathology (Impact Factor: 3.45). 02/2010; 56(3):356-63. DOI: 10.1111/j.1365-2559.2010.03486.x
Source: PubMed


To test the hypothesis that the published morphological criteria permit reliable segregation of small cell carcinoma of the lung (SCLC) and large cell neuroendocrine carcinoma (LCNEC) cases by determining the interobserver variation.
One hundred and seventy cases of SCLC, LCNEC and cases diagnosed as neuroendocrine lung carcinoma before LCNEC had been established as a diagnostic category were retrieved from the archives of the assessor's institutes. A representative haematoxylin and eosin section from each case was selected for review. Batches of cases were circulated among nine pathologists with a special interest in pulmonary pathology. Participants were asked to classify the cases histologically according to the 2004 World Health Organization (WHO) criteria. The diagnoses were collected and kappa values calculated. Unanimity of diagnosis was achieved for only 20 cases; a majority diagnosis was reached for 115 cases. In 35 cases no consensus diagnosis could be reached. There was striking variability amongst assessors in diagnosing SCLC and LCNEC. The overall level of agreement for all cases included in this study was fair (kappa=0.40).
Using non-preselected cases, the morphological WHO criteria for diagnosing SCLC and LCNEC leave room for subjective pathological interpretation, which results in imprecise categorization of SCLC and LCNEC cases.

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    • "Only a 40% unanimous agreement among five pathologists diagnosing LCNEC was accomplished in a reproducibility study by Travis et al. 21. Furthermore, in an interobserver variability study 12% unanimous diagnosis were made within nine pathologists 22. "
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    ABSTRACT: Background: Lung cancer still remains the leading cause of cancer for men after prostate cancer and breast cancer for women. Angiogenesis is considered a major microenvironment modifier. Material and methods: Demographic data and study design; The study is based on a collective of twenty representative specimens of each tumour entity (Typical Carcinoid, Atypical Carcinoid, Large-Cell Neuroendocrine Carcinoma , Small Cell Lung Cancer) for mRNA expression analysis. The following methods were performed: RNA Extraction and RNA Integrity Assessment, NanoString CodeSet Design and Expression Quantification, NanoString Data Processing and Statistical Analysis. Results: KDR rendered significant association to aggressiveness of the tumour and decreases with increasing malignancy (p=0.049). A decreased expression of HIF1A and KDR mRNA as associated with a higher risk of tumour invasion in vessels (HIF1A: p=0.034; KDR: p=0.029). FIGF and HIF1A expression levels are significantly associated with progression-free survival (FIGF: p= 0.021; HIF1A: p= 0.049). CRHR2 and FLT4 are stronger expressed in female than in male patients (CRHR2: p=0.024, FLT4: p=0.004). FIGF expression is still significant between LCNEC and SCLC (p=0.023). FLT4 and KDR show highly significant association to one of the analysed groups (FLT4: p=0.001; KDR: p=0.006). Additionally, HIF1A expression differs significantly between these focus cohorts (p=0.018). Conclusion: We should consider for clinical practice application which factors affect most the tumour growth and distal metastasis, thereafter investigate easy to administer drugs with low side effects. Probably a cluster system of therapy should be established where a drug targets simultaneously different pathways of the same origin.
    Journal of Cancer 05/2014; 5(6):465-71. DOI:10.7150/jca.9235 · 3.27 Impact Factor
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    • "Therefore, patients with LCNEC receive chemotherapy for treatment of non-small cell carcinoma or SCC, but its response to chemotherapy is still debatable.6 Although subtyping of neuroendocrine tumors is dependent upon the morphologic features and the amount of mitotic activity, reproducibility rates among pathologists are relatively low.7,8 Therefore, a critical need exists to identify further diagnostic clues. "
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    ABSTRACT: Few studies on how to diagnose pulmonary neuroendocrine tumors through morphometric analysis have been reported. In this study, we measured and analyzed the characteristic parameters of pulmonary neuroendocrine tumors using an image analyzer to aid in diagnosis. Sixteen cases of typical carcinoid tumor, 5 cases of atypical carcinoid tumor, 15 cases of small cell carcinoma, and 51 cases of large cell neuroendocrine carcinoma were analyzed. Using an image analyzer, we measured the nuclear area, perimeter, and the major and minor axes. The mean nuclear area was 0.318±0.101 µm2 in typical carcinoid tumors, 0.326±0.119 µm2 in atypical carcinoid tumors, 0.314±0.107 µm2 in small cell carcinomas, and 0.446±0.145 µm2 in large cell neuroendocrine carcinomas. The mean nuclear circumference was 2.268±0.600 µm in typical carcinoid tumors, 2.408±0.680 µm in atypical carcinoid tumors, 2.158±0.438 µm in small cell carcinomas, and 3.247±1.276 µm in large cell neuroendocrine carcinomas. All parameters were useful in distinguishing large cell neuroendocrine carcinoma from other tumors (p=0.001) and in particular, nuclear circumference was the most effective (p=0.001). Pulmonary neuroendocrine tumors showed nuclear morphology differences by subtype. Therefore, evaluation of quantitative nuclear parameters improves the accuracy and reliability of diagnosis.
    The Korean Journal of Pathology 02/2013; 47(1):16-20. DOI:10.4132/KoreanJPathol.2013.47.1.16 · 0.17 Impact Factor
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    • "Our results provided an objective explanation for the considerable levels of interobserver variability in the diagnosis of high-grade pulmonary NE carcinomas, with kappa values that ranged from 0.35 (fair agreement) to 0.81 (almost perfect agreement). Den Bakker et al.4 reported that there was striking variability amongst observers in diagnosing SCLC and LCNEC with variable agreement, from weak agreement (kappa value=0.19) to good agreement (kappa value=0.54), and the overall level of agreement for all cases was fair (kappa value=0.40). "
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    ABSTRACT: Distinguishing small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung is difficult with little information about interobserver variability. One hundred twenty-nine cases of resected SCLC and LCNEC were independently evaluated by four pathologists and classified according to the 2004 World Health Organization criteria. Agreement was regarded as "unanimous" if all four pathologists agreed on the classification. The kappa statistic was calculated to measure the degree of agreement between pathologists. We also measured cell size using image analysis, and receiver-operating-characteristic curve analysis was performed to evaluate cell size in predicting the diagnosis of high-grade neuroendocrine (NE) carcinomas in 66 cases. Unanimous agreement was achieved in 55.0% of 129 cases. The kappa values ranged from 0.35 to 0.81. Morphometric analysis reaffirmed that there was a continuous spectrum of cell size from SCLC to LCNEC and showed that tumors with cells falling in the middle size range were difficult to categorize and lacked unanimous agreement. Our results provide an objective explanation for considerable interobserver variability in the diagnosis of high-grade pulmonary NE carcinomas. Further studies would need to define more stringent and objective definitions of cytologic and architectural characteristics to reliably distinguish between SCLC and LCNEC.
    02/2012; 46(1):42-7. DOI:10.4132/KoreanJPathol.2012.46.1.42
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