Interobserver variation in the classification of thymic tumours--a multicentre study using the WHO classification system.

AIMS: To test the reproducibility of the current World Health Organization (WHO) classification of thymic epithelial tumours and to determine the level of interobserver variation within a group of pathologists, all with experience and expertise in thoracic pathology. METHODS AND RESULTS: Ninety-five thymic tumours were circulated to a group of 17 pathologists in the UK and The Netherlands over a 1-year period. Participants were asked to classify them according to WHO criteria. The diagnoses were subjected to statistical analysis and kappa values calculated. The overall level of agreement was moderate (kappa 0.45). When the categories were reduced in number by creating two groups, (A + AB + B1 + B2 and B3 + C), the level of agreement increased to 0.62. An alternative grouping (A + AB + B1 and B2 + B3 + C) increased it slightly further. The best agreement was in tumour types A and AB. Difficulties arose in distinguishing B1 tumours from B2 tumours and B2 tumours from B3 tumours. CONCLUSIONS: Although the WHO system describes a number of well-defined tumour types with clear diagnostic criteria, the overall level of agreement was moderate and improved if some groups were amalgamated.

CDKN2B methylation status and isolated chromosome 7 abnormalities predict responses to treatment with 5-azacytidine.

5-Azacytidine, a DNA methyl transferase inhibitor, is effective in patients with myelodysplastic syndromes (MDS). Whether responses to 5-Azacytidine are achieved by demethylation of key genes or by cytotoxicity is unclear. Of 34 patients with MDS or acute myeloid leukaemia (AML) treated with 5-Azacytidine, 7 achieved complete remissions (CR) (21%) and 6 achieved haematological improvement. All six had less than 5% bone marrow (BM) blasts at the time of haematological improvements (HI) (2 had pre-existing refractory anaemia (RA), 4 had refractory anaemia with excess blasts (RAEB)). A further patient with RAEB had blast reduction to less than 5% without HI. Five of the seven (71%) complete responders had chromosome 7 abnormalities. BM CR predicted longer overall survival (OS) (median 23 versus 9 months, P=0.015). Bisulphite genomic sequencing (BGS) of the CDKN2B (p15(INK4b)) promoter showed low level, heterogeneous pretreatment methylation (mean 12.2%) in 14/17 (82%) patients analysed. Lower baseline methylation occurred in responders (9.8% versus 16.2% in non-responders P=0.07). No response was seen in patients with >24% methylation, in whom p15(INK4b) mRNA was not expressed. 5-Azacytidine reduced CDKN2B methylation by mean 6.8% in 8/17 (47%) patients, but this did not correlate with response. At 75 mg/m(2), cell death (reduced BM cellularity (P=0.001) and increased apoptosis (P=0.02)) rather than demethylation of CDKN2B correlates with response. Patients with >24% methylation may benefit from alternative dosing or combination strategies.

Nonfatal congenital alveolar dysplasia due to abnormalities of NO synthase isoforms.

Congenital alveolar dysplasia (CAD) is a rare disorder thought to represent alveolar growth arrest at the canalicular stage of development. An infant with CAD diagnosed on lung biopsy is reported, her respiratory problems resolved spontaneously and she was doing well at follow-up. The infant additionally suffered from systemic hypertension and hypertrophic pyloric stenosis. In conclusion, we speculate that the association of CAD with systemic hypertension and hypertrophic pyloric stenosis might be explained by abnormalities of isoforms of nitric oxide synthase (NOS) resulting in congenital deformities involving smooth muscles.

Immunohistochemical markers in the differentiation of thymic and pulmonary neoplasms.

AIMS: The histopathological features of some thymic neoplasms overlap with those of pulmonary squamous and large-cell undifferentiated carcinomas, and identification of the primary site may be difficult on routine staining. We have assessed a panel of antibodies that may help to distinguish between neoplasms from these two sites. METHODS AND RESULTS: Antibodies identifying cytokeratin 7 (CK7), CD5, CD10, CD1a and thyroid transcription factor-1 (TTF-1) were applied to a series of 20 thymic neoplasms (thymic carcinomas, atypical thymomas and thymomas), 10 primary squamous cell carcinomas of the lung and 10 large-cell undifferentiated carcinomas of the lung. Staining for TTF-1 was positive in 3/10 large-cell undifferentiated carcinomas, but negative in all other tumours. CD5 showed strong membranous staining in 3/6 thymic carcinomas and 1/14 thymomas, but only focal staining in 1/20 pulmonary carcinomas. CD1a was consistently positive in thymic lymphocytes in both typical and atypical thymomas, but only focally in 1/6 thymic carcinomas. CD1a stained dendritic cells in 7/20 pulmonary carcinomas, but did not stain lymphocytes. Staining for CK7 and CD10 did not aid in differentiating between a pulmonary or thymic origin of the tumour. CONCLUSION: Staining for TTF-1, CD5 and CD1a have potential use in distinguishing between pulmonary and thymic neoplasms.