Document Detail


Dedifferentiation in gastrointestinal stromal tumor to an anaplastic KIT-negative phenotype: a diagnostic pitfall: morphologic and molecular characterization of 8 cases occurring either de novo or after imatinib therapy.
MedLine Citation:
PMID:  23348204     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Most gastrointestinal stromal tumors (GISTs) can be recognized by their monotonous cytologic features and overexpression of KIT oncoprotein. Altered morphology and loss of CD117 reactivity has been described previously after chronic imatinib treatment; however, this phenomenon has not been reported in imatinib-naive tumors. Eight patients with abrupt transition from a classic CD117-positive spindle cell GIST to an anaplastic CD117-negative tumor were investigated for underlying molecular mechanisms of tumor progression. Pathologic and molecular analysis was performed on each of the 2 components. Genomic DNA polymerase chain reaction for KIT, PDGFRA, BRAF, and KRAS hot spot mutations and fluorescence in situ hybridization for detecting KIT gene copy number alterations were performed. TP53 mutational analysis was performed in 5 cases. There were 7 men and 1 woman, with an age range of 23 to 65 years. Five of the primary tumors were located in the stomach, and 1 case each originated in the small bowel, colon, and rectum. In 3 patients, the dedifferentiated component occurred in the setting of imatinib resistance, whereas the remaining 5 occurred de novo. The dedifferentiated component had an anaplastic appearance, including 1 angiosarcomatous phenotype, with high mitotic activity and necrosis, and showed complete loss of CD117 (8/8) and CD34 (5/8) expression and de novo expression of either cytokeratin (4/8) or desmin (1/8). There was no difference in the KIT genotype between the 2 components. However, 2 imatinib-resistant tumors showed coexistence of KIT exon 11 and exon 13 mutations. Fluorescence in situ hybridization showed loss of 1 KIT gene in 3 cases and low-level amplification of KIT in 2 other cases in the CD117-negative component, compared with the CD117-positive area. TP53 mutation was identified in 1/5 cases tested, being present in both components. In summary, dedifferentiation in GIST may occur either de novo or after chronic imatinib exposure and can represent a diagnostic pitfall. This phenomenon is not related to additional KIT mutations, but might be secondary to genetic instability, either represented by loss of heterozygosity or low level of KIT amplification.
Authors:
Cristina R Antonescu; Salvatore Romeo; Lei Zhang; Khedoudja Nafa; Jason L Hornick; Gunnlaugur Petur Nielsen; Mari Mino-Kenudson; Hsuan-Ying Huang; Juan-Miguel Mosquera; Paolo A Dei Tos; Christopher D M Fletcher
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The American journal of surgical pathology     Volume:  37     ISSN:  1532-0979     ISO Abbreviation:  Am. J. Surg. Pathol.     Publication Date:  2013 Mar 
Date Detail:
Created Date:  2013-02-07     Completed Date:  2013-04-09     Revised Date:  2014-03-06    
Medline Journal Info:
Nlm Unique ID:  7707904     Medline TA:  Am J Surg Pathol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  385-92     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adult
Aged
Antineoplastic Agents / therapeutic use
Benzamides
Cell Dedifferentiation*
DNA Mutational Analysis
Female
Gastrointestinal Stromal Tumors / genetics,  metabolism*,  pathology*
Gene Dosage
Genes, p53
Humans
Immunohistochemistry
In Situ Hybridization, Fluorescence
Male
Middle Aged
Mutation
Phenotype
Piperazines / therapeutic use
Polymerase Chain Reaction
Proto-Oncogene Proteins c-kit / genetics,  metabolism*
Pyrimidines / therapeutic use
Young Adult
Grant Support
ID/Acronym/Agency:
P01CA47179/CA/NCI NIH HHS; P50 CA 140146-01/CA/NCI NIH HHS; P50 CA140146/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Benzamides; 0/Piperazines; 0/Pyrimidines; BKJ8M8G5HI/imatinib; EC 2.7.10.1/Proto-Oncogene Proteins c-kit
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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