OBJECTIVETo study the clinicopathologic features and possible molecular mechanisms of adenoid cystic carcinoma with high-grade transformation.

METHODSFour cases of adenoid cystic carcinoma with high-grade transformation were enrolled into the study. Immunohistochemical study for smooth muscle actin, p63, p53 and Ki-67 was carried out. C-myc gene status was analyzed by fluorescence in-situ hybridization.

RESULTSThere were altogether 3 males and 1 female. The mean age of the patients was 55.5 years. Two patients died 17 months and 29 months after operation, respectively. One patient had distant metastasis 23 months after operation and was still alive at 26-month follow up. The remaining patient remained tumor free at 3-month follow up. High-grade transformation in adenoid cystic carcinoma presented either as poorly differentiated adenocarcinoma or undifferentiated carcinoma. Histologic examination showed sheets of pleomorphic tumor cells occupying more than one low-power field. The high-grade carcinoma cells showed increased nuclear-cytoplasmic ratio, prominent eosinophilic nucleoli and active mitosis (ranging from 8 to 25 per high-power field). Comedo necrosis was observed in 2 cases and multiple foci of calcifications in 3 cases. Immunohistochemical study demonstrated loss of myoepithelial differentiation, overexpression of p53 and high proliferative index by Ki-67. No c-myc translocation or copy-number changes were observed.

CONCLUSIONSHigh-grade transformation in adenoid cystic carcinoma is rare. The histopathologic features are rather distinctive and the biologic behavior is aggressive. C-myc gene mutation does not seem to play a key role in the pathogenesis.

Actins ; metabolism ; Adenocarcinoma ; genetics ; metabolism ; pathology ; Adult ; Aged ; Carcinoma ; genetics ; metabolism ; pathology ; Carcinoma, Adenoid Cystic ; genetics ; metabolism ; pathology ; Cell Transformation, Neoplastic ; Eye Neoplasms ; genetics ; metabolism ; pathology ; Female ; Follow-Up Studies ; Genes, myc ; Humans ; Ki-67 Antigen ; metabolism ; Lacrimal Apparatus ; Lacrimal Apparatus Diseases ; genetics ; metabolism ; pathology ; Lung Neoplasms ; genetics ; metabolism ; pathology ; Male ; Maxillary Sinus Neoplasms ; genetics ; metabolism ; pathology ; Membrane Proteins ; metabolism ; Middle Aged ; Mutation ; Parotid Neoplasms ; genetics ; metabolism ; pathology ; Survival Rate ; Tumor Suppressor Protein p53 ; metabolism

OBJECTIVEAllgrove syndrome is a rare autosomal recessive disorder characterized by the triad of adrenal insufficiency, achalasia and alacrima and many cases have multi-systems disorder: endocrine, gastrointestinal tract, eyes and nervous system. This syndrome is also known as achalasia-addisonianism-alacrima syndrome or triple A syndrome. Allgrove syndrome is now known to be caused by mutations of AAAS gene encoding the aladin protein. In the present paper, we report a Chinese mainland girl with Allgrove syndrome with mutations in the AAAS gene.

METHODThe patient was a 7-year-old girl complained of coma and dark skin; she was treated as Addison disease for 2 years and had vomiting for 9 months before the second admission. Gene analysis was performed after extracting genomic DNA by amplification and sequencing of the specific fragments of AAA gene.

RESULTSThe patient was confirmed to have adrenal insufficiency at the age of 5 years and 6 months. During the second hospitalization, she was found to have a remarkable brisk reflexion, bilateral optic nerve atrophy, alacrima and achalasia besides ACTH resistance. The girl was born to consanguineous parents. Based on these findings, she was diagnosed as having Allgrove syndrome. Mutation analysis revealed a novel homozygous deletion of a single G, c.771delG, in exon 8 of the AAAS gene. This frame shift mutation was predicted to create a premature stop codon at locus 290, p.R258GfsX33, leading to a truncated and non-functioning aladin protein. Both the parents were heterozygous for the mutation.

CONCLUSIONThe clinical manifestations and AAAS gene mutations analysis confirmed the diagnosis of Allgrove syndrome. Gene analysis indicated that this syndrome is an autosomal recessive inherent disorder. ALADIN is significant for the normal cell function. When compared with reported cases, it seems that there are no remarkable relation between gene mutation loci and clinical manifestations in Allgrove syndrome.

Adrenal Insufficiency ; genetics ; Adrenocorticotropic Hormone ; blood ; China ; Consanguinity ; DNA ; analysis ; DNA Mutational Analysis ; Esophageal Achalasia ; genetics ; Exons ; Female ; Genetic Diseases, Inborn ; genetics ; Humans ; Lacrimal Apparatus Diseases ; genetics ; Mutation ; Nerve Tissue Proteins ; genetics ; Nuclear Pore Complex Proteins ; genetics ; Optic Atrophy ; genetics ; physiopathology

Triple A syndrome is a rare genetic disorder caused by mutations in the achalasia-addisonianism-alacrima syndrome (AAAS) gene which encodes a tryptophan aspartic acid (WD) repeat-containing protein named alacrima-achalasia-adrenal insufficiency neurologic disorder (ALADIN). Northern blot analysis shows that the 2.1 kb AAAS mRNA is expressed in various tissues with stronger expression in testis and pancreas. We show that human ALADIN is a protein with an apparent molecular weight of 60 kDa, and expressed in the adrenal gland, pituitary gland and pancreas. Furthermore, biochemical analysis using anti-ALADIN antibody supports the previous finding of the localization of ALADIN in the nuclear membrane. The mutations S544G and S544X show that alteration of S544 residue affects correct targeting of ALADIN to the nuclear membrane.
Adrenal Insufficiency/*genetics ; Antibodies/immunology ; Cloning, Molecular ; DNA, Complementary/genetics ; Esophageal Achalasia/*genetics ; Gene Expression Profiling ; Hela Cells ; Humans ; Lacrimal Apparatus Diseases/*genetics ; Mutagenesis, Site-Directed ; Nerve Tissue Proteins/*analysis/*genetics/immunology ; Nuclear Pore/chemistry ; Nuclear Pore Complex Proteins/*analysis/*genetics/immunology ; RNA, Messenger/analysis/genetics ; Syndrome ; Tissue Distribution