Christopher R Chitambar — Page 2

PubMed2002

Clinical, histopathologic, and biologic features of pleomorphic lobular (ductal-lobular) carcinoma in situ of the breast: a report of 24 cases.

We reviewed 10 cases of pleomorphic lobular (ductal lobular) carcinoma in situ (PL/DLCIS) of the breast and compared them with 14 cases of pleomorphic lobular carcinoma in situ (PLCIS) found in association with invasive pleomorphic lobular carcinoma. The histologic features; immunohistochemical staining for estrogen receptors (ERs), p53, Ki67, E-cadherin, and gross cystic disease fluid protein-15 (GCDFP-15); and results of fluorescence in situ hybridization for HER-2/neu gene amplification were evaluated in all 24 cases. Histologically, PL/DLCIS cells were similar to those of PLCIS with invasion in that they were discohesive and medium to large in size with moderate to marked nuclear pleomorphism, small to prominent nucleoli, and moderate to abundant eosinophilic or vacuolated cytoplasm. In both groups, central necrosis was present in a small number of cases, and classic LCIS coexisted with the in situ lesion in less than half of the cases; in situ carcinomas were positive for ERs in 23 (100%) of 23 cases, p53 in 6 (25%) of 24 cases, and GCDFP-15 in 14 (74%) of 19 cases. The percentage of Ki67-positive tumor nuclei indicated moderate to high (more than 20%) proliferative activity in 8 (47%) of 17 cases. Immunostaining for E-cadherin was negative in all 24 cases. HER-2/neu gene amplification was observed in 1 (4%) of 23 cases. In cases with associated invasion, PLCIS had cytologic features and immunostaining patterns similar to those of the invasive pleomorphic component. Seven of the 10 patients who had PL/DLCIS without invasion underwent lumpectomy or simple mastectomy. Six of these patients had no evidence of disease in follow-up periods ranging from 4 to 32 months; the seventh patient developed recurrent disease 12 months after undergoing lumpectomy. We conclude that the cytologic features and biomarker expression profile of PL/DLCIS are similar to those of PLCIS with invasion but somewhat different from those of classic LCIS and ductal carcinoma in situ. Long-term follow-up studies are needed to further define the natural history of PL/DLCIS and its optimal management.

Adult↗

PubMedDate not supplied

Genomic imbalances in drug-resistant T-cell acute lymphoblastic CEM leukemia cell lines.

Ten T-cell acute lymphoblastic (T-ALL) CEM cell lines selected for resistance toward methotrexate (CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, CEM/MTX5000PGA, CEM/MTXR1, CEM/MTXR2, and CEM/MTXR3), doxorubicin (CEM/ADR5000), vincristine (CEM/VCR1000), or hydroxyurea (CEM/HUR90), respectively, and parental drug-sensitive CCRF-CEM cells were analyzed using comparative genomic hybridization. Most genomic imbalances were not specific for drug resistance, as they were found in both parental and drug-resistant lines. Three aberrations were common to all or most cell lines analyzed: dim(5q35), dim(9p21p24), and enh(20q). We were concerned on those imbalances which were specifically present in drug-resistant but not in drug-sensitive cells. All methotrexate-resistant cell lines were characterized by an enhancement or an amplification of 5q13. The methotrexate resistance-conferring dihydrofolate reductase (DHFR) gene is located at this locus. Gain of DHFR was verified by PCR analyses. CEM/MTX60PGA, CEM/MTX140LV, CEM/MTX1500LV, and CEM/MTX5000PGA showed enh(14q21qter) and CEM/MTX5000PGA amp(5p13p15.2). These two loci harbor the methylenetetrahydrofolate dehydrogenase (MTHFD1) and 5'-methyltetrahdrofolate-homocysteine methyltransferase reductase (MTRR) genes, both of which are involved in folate metabolism. Their gain indicates a role in methotrexate resistance. A loss of 4q35 was found in CEM/MTXR2, CEM/MTXR3, and CEM/ADR5000 where the proapoptotic caspase-3 gene is located. The thioredoxin (TXN) locus 9q31 was enhanced in CEM/ADR5000 and CEM/MTX5000PGA cells. 2p22pter was increased in hydroxyurea-resistant CEM/HUR90 cells. Ribonucleotide reductase polypeptide M2 (RRM2), which confers resistance to hydroxyurea, resides at this locus. Other specific genomic imbalances in drug-resistant cell lines were dim(1p36.5), enh(4p), dim(8p22pter), enh(12p13), dim(17p), enh(18q12), enh(21q22.2), dim(21q22.2), and dim(22q13). All genomic imbalances were subjected to hierarchical cluster analysis and clustered image mapping to identify profiles of chromosomal aberrations in the cell lines. The obtained dendrograms allowed separation of imbalances common to all or most cell lines from other more individual aberrations. Furthermore, methotrexate-resistant cell lines clustered together. Our future efforts will be directed toward those imbalances which implicate still unknown candidate drug resistance genes.

Antineoplastic Agents↗