Skov BG, Krasnik M, LantueJoul S, Skov T, Brambilla EReclassification of neuroendocrine tumors improves the separation of carcinoids and the prediction of survival. J Thorac Oncol 12: 1410-1415

Department of Pathology, Herlev University Hospital, division Gentofte, Copenhagen, Denmark.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer (Impact Factor: 5.28). 01/2009; 3(12):1410-5. DOI: 10.1097/JTO.0b013e31818e0dd4
Source: PubMed


The classification of neuroendocrine lung tumors has changed over the last decades. Reliable diagnoses are crucial for the quality of clinical databases. The purpose of this study is to determine to which extent the use of different diagnostic criteria of neuroendocrine lung tumors has influenced the classification of these tumors. The prognostic information of tumor, node, metastasis descriptors was also evaluated.
We retrieved 110 tumors from the period 1989 to 2007. All tumors were reclassified according to the World Health Organization classification of 2004. Tumor, node, metastasis descriptors were evaluated.
By reclassification, the diagnoses on 48 tumors (44%) were changed. More diagnoses were changed in the older part of the material. A significantly different survival was shown for all patients in relation to tumor size (p < 0.0001). An endobronchial component was seen in 54%, 31%, and 11% of typical carcinoid, atypical carcinoid, and large cell neuroendocrine carcinoma, respectively with no impact on survival (p = 0.90). For all included patients the survival was significantly worse for patients having metastasis to N1 nodes as compared with N0 (p = 0.03). However, the number of removed lymph nodes were insufficient for definitive determination of the prognostic impact of node metastases. Regarding the revised diagnoses, a significant difference in survival between typical carcinoid, atypical carcinoid, large cell neuroendocrine carcinoma and small cell carcinoma was noted (p < 0.005).
Tumors must be rediagnosed before entering a central database. Tumor and node seem to be useful predictors of survival.

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    • "Histologically, it is possible to distinguish between TC and AC according to the number of mitosis and the presence of necrosis: TC is characterised byo2 mitoses per 2 mm 2 (10 HPF) with no necrosis, while AC is defined by a number of mitoses between 2 and 10 per 2 mm 2 and/or coagulative necrosis. Pathologists referent for these malignances (Scott, 2003; Skov et al, 2008) acknowledge such diagnostic parameters as very difficult to assess, because depending on the size and quality of the specimens. Furthermore, prolonged or inadequate fixation, thick sections, suboptimal staining, or the presence of extensive necrosis, fibrous or inflammatory stroma, and crush artefacts can considerably hamper the evaluation, clearly suggesting that the definition of easily reproducible diagnostic tools is a major clinical need. "
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    ABSTRACT: Background: Classification of lung carcinoids into typical and atypical is a diagnostic challenge since no immunohistochemical tools are available to support pathologists in distinguishing between the two subtypes. A differential diagnosis is essential for clinicians to correctly discuss therapy, prognosis and follow-up with patients. Indeed, the distinction between the two typical and atypical subtypes on biopsies/cytological specimens is still unfeasible and sometimes limited also after radical surgeries. By comparing the gene expression profile of typical (TC) and atypical carcinoids (AC), we intended to find genes specifically expressed in one of the two subtypes that could be used as diagnostic markers. Methods: Expression profiling, with Affymetrix arrays, was performed on six typical and seven atypical samples. Data were validated on an independent cohort of 29 tumours, by means of quantitative PCR and immunohistochemistry (IHC). Results: High-throughput gene expression profiling was successfully used to identify a gene signature specific for atypical lung carcinoids. Among the 273 upregulated genes in the atypical vs typical subtype, GC (vitamin D-binding protein) and CEACAM1 (carcinoembryonic antigen family member) emerged as potent diagnostic markers. Quantitative PCR and IHC on a validation set of 17 ACs and 12 TCs confirmed their reproducibility and feasibility. Conclusions: GC and CEACAM1 can distinguish between TC and AC, defining an IHC assay potentially useful for routine cytological and histochemical diagnostic procedures. The high sensitivity and reproducibility of this new diagnostic algorithm strongly support a further validation on a wider sample size.
    British Journal of Cancer 02/2014; 110(5). DOI:10.1038/bjc.2014.41 · 4.84 Impact Factor
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    • "In bronchopulmonary carcinoids Ki-67 score has been reported to be around 0.2–1.1% in TC and 0 .3–20.3% in AC. Several studies reported an association between high Ki-67 expression and a worse prognosis (el-Naggar et al., 1991; Costes et al., 1995; Slodkowska et al., 1998; Beasley et al., 2000; Laitinen et al., 2000; Kobayashi et al., 2004; Faggiano et al., 2008; Rugge et al., 2008; Skov et al., 2008). Data available in literature show a considerable variability "
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    ABSTRACT: Introduction: Histological distinction between typical and atypical bronchopulmonary carcinoids is based on mitotic activity and necrosis. Regardless of these two parameters, outcome after surgery is often unpredictable. In this study the prognostic value of different clinico-pathological factors was retrospectively analyzed in a large series of patients with bronchopulmonary carcinoid. Materials and Methods: The long-term post-surgical outcome of 106 radically treated patients affected by bronchopulmonary carcinoid from two Italian centers was correlated with tumor characteristics assessed by combining conventional histology with a panel of immunohistochemical markers of neuroendocrine differentiation (chromogranin-A, NSE) and proliferation activity (Ki-67 score). Results: Carcinoids were assessed as typical (TC = 75; 70.8%) and atypical (AC = 31; 29.2%). Mean follow-up was 8.3 years (range: 0-20; median: 8.0). All cases expressed neuroendocrine markers. At univariate analysis, tumor recurrence [14/75 TC (18.7%), 15/31 AC (48.4%)] correlated with carcinoid histotype (P = 0.003), tumor size (P = 0.012), mitotic index (P = 0.044), Ki-67 score (P < 0.0001), and synchronous node metastasis (P = 0.037). Of these, Cox multivariate analysis confirmed only Ki-67 score as independent predictor of disease recurrence (P = 0.009). The best cut-off for Ki-67 score (calculated by ROC curves) discriminating recurrent vs non-recurrent disease was 4% (sensitivity 79.3%; specificity 83.8%; area under the curve 0.85). By stratifying patients according to this cut-off, a significantly different disease-free survival was found (log-rank test P < 0.0001). Conclusion: Ki-67 score accurately separates bronchopulmonary carcinoids in two well-distinct histo-prognostic categories. Ki-67 score predicts the patients outcome better than mitotic count, histotype, and tumor stage and it is therefore helpful in establishing the appropriate follow-up.
    Frontiers in Endocrinology 08/2011; 2:20. DOI:10.3389/fendo.2011.00020
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    ABSTRACT: Tumors with pure or incomplete neuroendocrine phenotype may arise everywhere in the human body, including non-neuroendocrine organs, and share several common ultrastructural, morphological and phenoptypical properties; however, they do not constitute a single, uniform entity, but rather represent a spectrum of lesions in which the degree of neuroendocrine differentiation matches the clinical behavior. This chapter reviews the common diagnostic and classification criteria of these tumors in the lung, breast, skin and urogenital tract, and reports the molecular data that have been related to morphology in order to better understand their histogenesis and biological properties, as well as to identify novel therapeutic targets. KeywordsNeuroendocrine-Divergent differentiation-Molecular biology-Lung-Breast-Skin-Urogenital tract-Tumor
    Endocrine Pathology:, 01/1970: pages 415-428;
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