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Global profiling of histone changes in some human cancers demonstrated that loss of histone H4 acetylation at lysine16 (H4KA16) and trimethylation at lysine 20 (H4KM20) was a common hallmark of cancer. It is not clear whether these epigenetic changes also exist in neuroendocrine carcinomas. We semiquantitatively analyzed 32 cases of lung neuroendocrine tumors (LNETs) immunohistochemically stained with H4KA16, H4KM20, and Ki67 antibodies by calculating cumulative scores based on the sum of the product of nuclear stain intensity (1-3) and percentages of positive cells in each category. H4KA16 and H4KM20 levels were compared among typical carcinoid (TC, 11), atypical carcinoid (AC, 6), large cell neuroendocrine carcinoma (LCNEC, 8), and small cell lung cancer (SCLC, 7) and correlated with histologic types and Ki67 labeling. Data were presented as mean±standard error of the mean and statistically analyzed by 1-way analysis of variance and Holm-Sidak method. Normal bronchiolar epithelium had relatively uniform and strong +3 positivity of H4KM20 and H4KA16, which was considered as internal positive controls. This uniformity, however, was gradually lost from low to high grades of LNETs. Semiquantitative analysis revealed that there were significant differences in cumulative scores of H4KA16 (TC, 2.36±0.03; AC, 2.04±0.08; LCNEC, 1.58±0.07; SCLC 1.32±0.05) among LNETs. For H4KM20, significant differences were only observed between low grade (TC, 2.49±0.05 and AC, 2.24±0.09) and high grade (LCNEC, 1.58±0.10 and SCLC 1.68±0.11) LNETs, but not within low or high grade LNETs. The Ki67 cumulative scores (TC, 0.06±0.02; AC, 0.41±0.08; LCNEC, 1.29±0.09; SCLC 1.83±0.06) were inversely correlated with both cumulative H4KA16 and H4KM20 scores by Pearson correlation. We conclude that progressive loss of H4KA16 and H4KM20 from low to high grade LNETs reflects the degree of differentiation and proliferative activity. These histone modifications may serve as tumor biomarkers that may aid in diagnosis and prediction of clinical outcome.

Approximately 5% to 15% of central nervous system metastases by solid tumors spread to the leptomeninges. Transmembrane MUC16 is thought to facilitate anchoring of metastases to other tissues particularly those expressing mesothelin such as pleura and peritoneum. Recently, we have demonstrated that mesothelin is also expressed in the leptomeninges. Mesothelin has a high affinity for MUC16 and mesothelin expressed by some adenocarcinomas. In this study, we evaluated MUC16 and mesothelin immunoreactivity by immunohistochemistry in 11 adenocarcinomas to the leptomeninges, 24 to mesothelin-negative brain, 8 metastases to mesothelin-expressing peritoneum/pleura, 22 to mesothelin-negative peripheral tissues, and 24 with no metastases. MUC16 was detected in 36% of leptomeningeal metastases and 10% of metastases to the brain. Adenocarcinoma metastases to mesothelin-expressing peritoneum or pleura exhibited extensive MUC16 in 75% of cases. In adenocarcinomas with local metastases to lymph nodes or no metastases, 53% or 38% had MUC16 immunoreactivity, respectively. Mesothelin-immunoreactivity was detected in 9% of metastases to the leptomeninges, 17% to the brain, none of the metastases to pleura/peritoneum, 50% of adenocarcinomas with local metastases to lymph nodes, etc, and 33% of adenocarcinomas without metastases. Mesothelin expression was significantly more common in nonmetastatic adenocarcinomas than in metastases to the pleura/peritoneum or leptomeninges. Our findings suggest that adenocarcinomas with MUC16 expression may have an increased risk for metastases to pleura/peritoneum but not the leptomeninges or brain.

Malignant solitary fibrous tumor (MSFT) is a rare neoplasm. Three cases of MSFT with unusual features, including 1 pleural and 2 extrapleural, are reported. A 64-year-old woman with a large right thoracic MSFT and episodes of severe hypoglycemia experienced resolution of her hypoglycemia immediately after resection of the MSFT. A 27-year-old woman with primary retroperitoneal MSFT had pulmonary metastases 10 months after resection of the primary tumor. A 54-year-old man with an intracranial solitary fibrous tumor suffered from multiple pulmonary metastases and local recurrence 21 and 28 months after resection of the primary tumor, respectively. All 3 cases of solitary fibrous tumor displayed malignant features. The tumor cells in each case were positive for CD34 and Bcl-2, but negative for cytokeratin, smooth muscle actin, S-100, and c-kit. In addition, the tumor cells in the case with concomitant hypoglycemia were strongly positive for insulin-like growth factor-II. The histopathologic diagnostic criteria for MSFT, the differential diagnosis with other spindle cell tumors, and the mechanism of MSFT-derived hypoglycemia via insulin-like growth factor-II are discussed.

It has been shown that tyrosine kinase oncoprotein c-kit and antiapoptotic molecule bcl-2 are overexpressed in several types of malignancy, including small cell carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC) of the lung. Whether these 2 molecules are coexpressed in lung neuroendocrine tumors has not been investigated. Here, we analyzed immunohistochemical results to determine expression and coexpression patterns of c-kit and bcl-2 in the spectrum of lung neuroendocrine tumors. Using a polyclonal antibody against c-kit and a monoclonal antibody against bcl-2, our data demonstrated that all 7 cases (100%) of SCLC included in this study were positive for both c-kit and bcl-2. Among 14 LCNECs, 7 (50%) stained positive for c-kit and 9 (64%) for bcl-2. All cases of high grade neuroendocrine carcinomas (SCLCs and LCNECs) that showed positive staining for c-kit coexpressed bcl-2. In contrast, all typical and atypical carcinoids (TC and AC) were negative for c-kit, and only 1 of 16 (6.3%) TCs and 1 of 6 (16.7%) ACs stained positive for bcl-2. These results indicate a progressive increase in the frequency of c-kit and bcl-2 expression and coexpression, from carcinoid tumors (TC and AC) to LCNEC and to SCLC. High grade neuroendocrine carcinomas are more likely to coexpress c-kit and bcl-2 when compared with carcinoid tumors. The high frequency of coexpression of these 2 molecules in high grade neuroendocrine carcinomas of the lung suggests that they may be involved in the carcinogenic pathway, given their important roles in carcinogenesis. Therapeutic targeting on both c-kit and bcl-2 molecules might be beneficial in the management of patients with high grade neuroendocrine carcinomas of the lung in the future.

D2-40 is a new monoclonal antibody recognizing podoplanin and it is selective for lymphatic endothelium. Several studies have confirmed the reliability of D2-40 in the diagnosis of pleural malignant mesothelioma, but the evaluation of this antibody in other pleural neoplasms is limited. The aim of this study was to determine the diagnostic value of D2-40 in segregation of malignant mesothelioma from other pleural or lung neoplasms. Sixty-seven cases, including 36 pleural malignant mesotheliomas, 15 solitary fibrous tumors, 13 pleomorphic carcinomas, and 3 synovial sarcomas, were immunohistochemically studied using a D2-40 monoclonal antibody. Twenty-five (21 epithelioid and 4 biphasic) of 36 (69%) malignant mesotheliomas and 2 of 15 (13%) solitary fibrous tumors were positive for D2-40. The difference of D2-40 positivity between these 2 types of tumor was significant (P

Parathyroid adenoma with prominent lymphocytic infiltrates is very rare, with only 8 previously reported cases in the English scientific literature. Cases with prominent lymphocytic infiltrates of ectopic (mediastinal) parathyroid adenomas have not been reported. The prominent lymphocytic infiltration may make the diagnosis difficult on frozen sections, even on permanent histologic sections. We herein describe a case of ectopic (mediastinal) parathyroid adenoma with prominent lymphocytic infiltration in a 29-year-old man with hyperparathyroidism for 4 years. Immunohistochemical studies were important in making such a diagnosis.