Malignant mixed tumors of the salivary gland: a study of loss of heterozygosity in tumor suppressor genes.

Carcinosarcomas and carcinoma ex pleomorphic adenoma of the salivary glands are rare tumors that fit into the broader category of malignant mixed tumors. Although most evidence has suggested that the different morphologic components arise from a common clonal origin, there are very few studies that have provided molecular evidence for this clonality. In this study, we examined a set of seven carcinosarcomas and four carcinomas ex pleomorphic adenoma for tumor suppressor gene loss of heterozygosity, in order to assess the clonal patterns in the varying components. Microdissection was performed to obtain each morphological component and tumor suppressor gene loci on 3p, 5q, 9p, 17p, 17q, and 18q were analyzed. The fractional allelic loss (FAL) was calculated for each area, and the different targets were compared for their molecular profile. The overall mean FAL of the malignant targets was 42%. In carcinosarcomas, the sarcomatous targets had a higher mean FAL than the carcinomatous targets (68 vs 46%, respectively) and in carcinomas ex pleomorphic adenoma, the mean FAL in the benign component was 11 vs 46% seen in the carcinomatous component. The most frequently lost genetic loci were p53 (17p13, 73%), nm23-H1 (17q21, 55%), and DCC (18q21, 50%). Loss of heterozygosity of 17q21 and 9p21 only occurred in carcinosarcomas and not in carcinomas ex pleomorphic adenoma. Within the carcinosarcomas, the mutational profiles were conserved between epithelial and sarcomatous areas. In carcinomas ex pleomorphic adenoma, loss of heterozygosity was uncommon in the benign component, but the mutations were conserved in the corresponding malignant areas. These results support the hypothesis that the carcinomatous and sarcomatous components of carcinosarcomas are clonally related. Furthermore, these data support prior studies that suggest a common clonal origin for the benign and malignant components of carcinomas ex pleomorphic adenoma.

Prenatal detection of deletion 6q13q15 in a complex karyotype.

OBJECTIVES: Prenatal diagnosis of a pregnancy with elevated maternal serum alpha-fetoprotein identified a karyotype with a complex chromosomal rearrangement, a Robertsonian translocation and a 6q deletion involving bands q13q15. Sonography identified mild IUGR, polyhydramnios and micrognathia. The infant presented with multiple congenital anomalies, primarily limited to the head and neck, including hypertelorism, broad nose, micrognathia, cleft palate, microglossia and low-set ears with microtia. METHODS: Amniocytes of the fetus and blood of the patient and her parents were analyzed by cytogenetics and fluorescence in situ hybridization. RESULTS: The karyotype on the fetus was 45,XX,t(3;21;20)(p12;q11.2;p11.2), del(6)(q13q15),der(13;14) (q10;q10)mat. CONCLUSION: The 13;14 Robertsonian translocation was inherited from the mother and the three-way translocation appeared to be balanced. The patient had facial dysmorphology similar to that which has been described in 6 previously reported cases with the same deletion involving 6q13q15. There was no recognizable abnormality of limbs or digits, and the autopsy did not identify defects involving the internal organs.

Comparative molecular analysis of loss of heterozygosity in adenocarcinoma in bile duct brushings and corresponding surgical pathology specimens.

BACKGROUND: Bile duct brushing is the procedure of choice for the assessment of neoplasia of the biliary and pancreatic ducts. Conventional cytopathologic evaluation has been reported to have high specificity but relatively low sensitivity. Although a number of molecular studies regarding biliary tract tissue specimens have been performed, to the authors' knowledge their precise applicability to cytopathology specimens has not been critically analyzed. METHODS: Bile duct brushing specimens with the cytopathologic diagnosis of "suspicious" or "positive for malignant cells" along with corresponding surgical pathology specimens demonstrating adenocarcinoma were searched for in the files of UPMC-Presbyterian Hospital for the years 1990-1996. Tumor cells from representative cytopathology and histology slides were microdissected and analyzed for loss of heterozygosity (LOH) in a panel of microsatellite markers. The results obtained from cytopathologic and surgical pathology specimens were compared. RESULTS: Eight paired surgical and cytopathology cases of adenocarcinoma involving the biliary tract were identified. The fractional allelic loss (FAL) for the surgical specimens (FAL-S) ranged from 12.5-71.4% and the FAL for the cytopathology specimens (FAL-C) ranged from 25-71.4%. However, when evaluating the actual loci of LOH, the concordance rate of the surgical and cytopathology specimens ranged from 71.4-100% (mean, 88.6%). Only 3 of the 8 cases (37.5%) were found to have identical matching of the LOH loci. CONCLUSIONS: Although the overall concordance rate of LOH in biliary cytology and surgical specimens by molecular analysis is relatively high, the issue of molecular tumoral heterogeneity must be considered if clinical decisions are to be based exclusively on cytopathologic analysis.