Cystatin A (
acid cysteine proteinase inhibitor; ACPI) is a natural inhibitor of
cysteine proteinases. It has been suggested that an inverse correlation exists between
cystatin A and malignant progression. We wanted to assess the
biological and clinical significance of
cystatin A in infiltrative
breast carcinoma by immunohistochemical staining.
Formalin-fixed
paraffin-embedded material from 440 cases treated during the years 1988-1991 was used in the study. After exclusion of patients with disseminated disease at diagnosis, previous contralateral
breast carcinoma, and absence of follow-up data, 384 patients could be included in the survival analysis. For immunohistochemical analysis of
cystatin A, we used monoclonal
cystatin A antibody WR-23/2/3/3, the binding of which was detected by the
avidin-
biotin-
peroxidase method. Immunohistochemical analysis of Bcl-2 and p53 was also done, and mitotic activity was evaluated. Positive staining for
cystatin A was found in 52 of 440 cases. The staining was irregular but showed irrefutably positive areas within neoplastic tissue. Most of the positive
tumors were of the ductal infiltrative type, but two were
mucinous carcinomas, one medullary and one
squamous cell carcinoma. No
lobular carcinomas showed positive staining. Focal
cystatin A positivity was seen in myoepithelial cells of benign ducts. Occasional apoptotic bodies within the
neoplasm showed strong positivity for
cystatin A.
Tumors positive for
cystatin A were of larger size and had higher mitotic activity than
cystatin A-negative
tumors.
Cystatin A was associated with negative Bcl-2 staining, but there was no statistically significant association between axillary lymph node status or p53 immunostaining. The risk for
breast cancer-related death was significantly higher in patients with
cystatin A-positive
tumors than in those with
cystatin A-negative ones. The risk increase was significant also in lymph node-negative patients. After adjusting for the effect of
tumor size, histological grade, and lymph node status,
cystatin A-positive patients still had a higher risk of death. Patients with
cystatin A and p53 coexpression had a higher risk of death than the other patients. The findings reveal a new variant of aggressive
breast cancer. This type of
carcinoma may develop during
tumor progression through genetic instability that allows
cystatin A expression and gives growth advantage to a clone of
tumor cells.