Extensive apoptosis in ductal carcinoma in situ of the breast.
BACKGROUND
More than 50% of breast ductal carcinomas in situ (DCIS) contain significant histologic necrosis, an important prognostic factor for determining recurrence and progression to invasive breast cancer. We have examined whether the mechanism of this spontaneous cell death might be apoptosis, a genetically encoded suicide pathway that may be triggered by various events including dysregulated cell proliferation.


METHODS
Twenty-five untreated DCIS cases accessioned at our institution were examined for subtype, grade, and presence of apoptosis using two criteria: (1) cellular morphology (shrinkage, nuclear condensation, fragmentation, apoptotic bodies, and lack of inflammatory component); and (2) terminal transferase (TUNEL) staining of DNA fragmentation, a characteristic though less specific feature of apoptosis. Immunohistochemical staining was also carried out to assess whether wild-type p53, a regulator of apoptosis, was associated with this cell death.


RESULTS
In all 19 cases with intraductal necrosis, cellular morphology was consistent with apoptotic death, despite its presence within sheets of "geographic necrosis." Additionally, the identical regions were all strongly TUNEL-positive. No evidence of TUNEL staining was seen in 5 Grade I DCIS cases without intraductal necrosis. Immunohistochemical staining suggested that this apoptosis was independent of p53 mutational status.


CONCLUSIONS
Extensive intraductal necrosis in DCIS is likely to represent apoptosis. However, it is unlikely that this apoptosis is regulated by p53. The apparently abundant apoptosis identified here, particularly in high grade DCIS, may be important in explaining why spontaneous cell death in DCIS is associated with a worse prognosis.
Bodis
S
S
Division of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
Siziopikou
K P
KP
Schnitt
S J
SJ
Harris
J R
JR
Fisher
D E
DE
D017209:Apoptosis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D002278:Carcinoma in Situ / Q000235:genetics / Q000473:pathology*; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000473:pathology*; D016923:Cell Death; D002455:Cell Division; D002467:Cell Nucleus / Q000648:ultrastructure; D004396:Coloring Agents; D004249:DNA Damage; D004253:DNA Nucleotidylexotransferase / Q000032:analysis; D003856:Deoxyuracil Nucleotides / Q000032:analysis; D018450:Disease Progression; D005260:Female; D016158:Genes, p53 / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D009154:Mutation / Q000235:genetics; D009336:Necrosis; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local / Q000473:pathology; D011379:Prognosis
D004396:Coloring Agents; D003856:Deoxyuracil Nucleotides; D004253:DNA Nucleotidylexotransferase