Fig. 1Representative histologic features of pulmonary high-grade neuroendocrine (NE) carcinomas. (A) Unanimous large cell neuroendocrine carcinoma (LCNEC) consists of organoid nesting of large, polygonal tumor cells that have abundant eosinophilic cytoplasm, coarsely granular chromatin, and prominent nucleoli. (B) Unanimous small cell lung carcinoma (SCLC) consists of a sheet-like growth pattern of tumor cells that are smaller than three lymphocytes. (B, inset) The cells have scant cytoplasm and finely granular chromatin pattern and inconspicuous nucleoli. (C) A debated case of high-grade NE carcinoma with a lack of unanimous agreement shows tumor cells with intermediate nuclear size larger than those seen in the tumor shown in (B) but smaller than those seen in the tumor shown in (A), which corresponds to three to four times the size of a lymphocyte (arrow). (D) Another case of high-grade NE carcinoma that lacks a unanimous diagnosis. Two observers diagnose it as SCLC due to the small tumor cell size (two to three times the size of a lymphocyte [arrow]), whereas the remaining two observers diagnose it as LCNEC, because the cytoplasm is not so scant, and a few nucleoli (arrowhead) and rosette-like pattern are observed.
Fig. 2Receiver operating characteristic (ROC) curve analysis using cell diameter for discriminating large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC). (A) At the cut-off value of 33.8 µm, cell diameter for unanimous LCNEC yields an area under the ROC curve (AUC) of 0.773 (95% confidence interval, 0.654 to 0.891), with 70.8% sensitivity and 73.8% specificity in discriminating unanimous LCNEC from other high-grade neuroendocrine (NE) carcinomas (unanimous SCLC and debated cases). (B) At the cut-off value of 28.6 µm, the cell diameter for unanimous SCLC yields an AUC of 0.905 (95% confidence interval, 0.826 to 0.985), with 80.0% sensitivity and 92.9% specificity in discriminating unanimous SCLC from other high-grade NE carcinomas (unanimous LCNEC and debated cases).
Table 1Agreement of the original diagnosis by each institute for all 129 cases studied
Table 2Interobserver agreement of four pathologists according to the kappa statistics for all 129 studied cases
Table 3Comparison of diagnosis by four pathologists with diagnosis according to the cut-off point using morphometric analysis for 66 studied cases
Table 4Comparison of diagnosis by four pathologists with diagnosis according to the cut-off point using morphometric analysis for 32 debated cases